6-oxo-1,6-dihydropyridine derivatives as inhibitors of MEK and methods of use thereof

ABSTRACT

Disclosed are compounds of the Formula V 
                         
and pharmaceutically acceptable salts and prodrugs thereof, wherein R 1 , R 2 , R 7 , R 8  and R 9 , and W are as defined in the specification. Such compounds are MEK inhibitors and useful in the treatment of hyperproliferative diseases, such as cancer and inflammation, and inflammatory conditions in mammals. Also disclosed are methods of using such compounds in the treatment of hyperproliferative diseases and inflammatory conditions in mammals and pharmaceutical compositions containing such compounds.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a Continuation of U.S. patent application Ser. No.11/132,164, which is a Continuation-in-Part of U.S. patent applicationSer. No. 10/992,612, filed Nov. 18, 2004, which application claims thebenefit of U.S. Provisional Application Ser. No. 60/523,270, filed Nov.19, 2003, each of which is incorporated herein by reference in itsentirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to a series of novel heterocyclic compounds thatare useful in the treatment of hyperproliferative diseases, such ascancer and inflammation, in mammals. This invention also relates to amethod of using such compounds in the treatment of hyperproliferativediseases in mammals, especially humans, and to pharmaceuticalcompositions containing such compounds.

2. Description of the state of the art

Cell signaling through growth factor receptors and protein kinases is animportant regulator of cell growth, proliferation and differentiation.In normal cell growth, growth factors, through receptor activation (i.e.PDGF or EGF and others), activate MAP kinase pathways. One of the mostimportant and most well understood MAP kinase pathways involved innormal and uncontrolled cell growth is the Ras/Raf kinase pathway.Active GTP-bound Ras results in the activation and indirectphosphorylation of Raf kinase. Raf then phosphorylates MEK1 and 2 on twoserine residues (S218 and S222 for MEK1 and S222 and S226 for MEK2) (Ahnet al., Methods in Enzymology, 2001, 332, 417-431). Activated MEK thenphosphorylates its only known substrates, the MAP kinases. ERK1 and 2.ERK phosphorylation by MEK occurs on Y204 and T202 for ERK1 and Y185 andT183 for ERK2 (Ahn et al., Methods in Enzymology, 2001, 332, 417-431).Phosphorylated ERK dimerizes and then translocates to the nucleus whereit accumulates (Khokhlatchev et al., Cell, 1998, 93, 605-615). In thenucleus, ERK is involved in several important cellular functions,including but not limited to nuclear transport, signal transduction. DNArepair, nucleosome assembly and translocation, and mRNA processing andtranslation (Ahn et al., Molecular Cell, 2000, 6, 1343-1354). Overall,treatment of cells with growth factors leads to the activation of ERK1and 2 which results in proliferation and, in some cases, differentiation(Lewis et al., Adv. Cancer Res., 1998, 74, 49-139).

In proliferative diseases, genetic mutations and/or overexpression ofthe growth factor receptors, downstream signaling proteins, or proteinkinases involved in the ERK kinase pathway lead to uncontrolled cellproliferation and, eventually, tumor formation. For example, somecancers contain mutations which result in the continuous activation ofthis pathway due to continuous production of growth factors. Othermutations can lead to defects in the deactivation of the activatedGTP-bound Ras complex, again resulting in activation of the MAP kinasepathway. Mutated, oncogenic forms of Ras are found in 50% of colonand >90% pancreatic cancers as well as many others types of cancers(Kohl et al., Science. 1993, 260, 1834-1837). Recently, bRaf mutationshave been identified in more than 60% of malignant melanoma (Davies, H.et al., Nature. 2002, 417, 949-954). These mutations in bRaf result in aconstitutively active MAP kinase cascade. Studies of primary tumorsamples and cell lines have also shown constitutive or overactivation ofthe MAP kinase pathway in cancers of pancreas, colon, lung, ovary andkidney (Hoshino. R. et al., Oncogene. 1999, 15, 813-822). Hence, thereis a strong correlation between cancers and an overactive MAP kinasepathway resulting from genetic mutations. As constitutive oroveractivation of MAP kinase cascade plays a pivotal role in cellproliferation and differentiation, inhibition of this pathway isbelieved to be beneficial in hyperproliferative diseases. MEK is a keyplayer in this pathway as it is downstream of Ras and Raf. Additionally,it is an attractive therapeutic target because the only known substratesfor MEK phosphorylation are the MAP kinases, ERK1 and 2. Inhibition ofMEK has been shown to have potential therapeutic benefit in severalstudies. For example, small molecule MEK inhibitors have been shown toinhibit human tumor growth in nude mouse xenografts, (Seboll-Leopold etal., Nature-Medicine. 1999, 5 (7), 810-816; Trachet et al., AACR Apr.6-10, 2002, Poster #5426; Tecle, H., IBC 2nd International Conference ofProtein Kinases. Sep. 9-10, 2002), block sialic allodynia in animals (WO01/05390) and inhibit growth of acute myeloid leukemia cells (Milella etal., J. Clin. Invest. 2001, 10H (6), 851-859).

Small molecule inhibitors of MEK have been disclosed, including in U.S.Patent Publication Nos. 2003/0232869, 2004/0116710, and 2003/0216460,and U.S. patent application Ser. Nos. 10/654,580 and 10/929,295, each ofwhich is hereby incorporated by reference. At least fifteen additionalpatent applications have appeared in the last several years. See, forexample: U.S. Pat. No. 5,525,625; WO 98/43960; WO 99/01421; WO 99/01426;WO 00/41505; WO 00/42002; WO 00/42003; WO 00/41994; WO 00/42022; WO00/42029; WO 00/68201; WO 01/68619; WO 02/06213; WO 03/077914; and WO03/077855.

SUMMARY OF THE INVENTION

This invention provides novel heterocyclic compounds, andpharmaceutically acceptable salts and prodrugs thereof which are usefulin the treatment of hyperproliferative diseases. Specifically, oneembodiment of the present invention relates to MEK inhibitors ofFormulas I-V:

and tautomers, metabolites, resolved enantiomers, diastereomers,solvates and pharmaceutically acceptable salts and prodrugs thereof,wherein:

X is N or CR¹⁰;

Y is NR³, O, S, S(O), S(O)₂, C(O) or CH₂;

R¹, R², R⁸, and R⁹ are independently hydrogen, hydroxy, halogen, cyano,nitro, trifluoromethyl, difluoromethyl, fluoromethyl, fluoromethoxy,difluoromethoxy, trifluoromethoxy, azido, —SR¹¹, —OR³, —C(O)R³,—C(O)OR³, —NR⁴C(O)OR⁶, —OC(O)R³, —NR⁴SO₂R⁶, —SO₂NR³R⁴, —NR⁴C(O)R³,—C(O)NR³R⁴, —NR⁵C(O)NR³R⁴, —NR⁵C(NCN)NR³R⁴, —NR³R⁴, C₁-C₁₀ alkyl, C₂-C₁₀alkenyl, C₂-C₁₀, alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkylalkyl,—S(O)_(j)(C₁-C₆ alkyl), —S(O)_(j)(CR⁴R⁵)_(m)-aryl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl,—O(CR⁴R⁵)_(m)-aryl, —NR⁴(CR⁴R⁵)_(m)-aryl, —O(CR⁴R⁵)_(m)-heteroaryl,—NR⁴(CR⁴R⁵)_(m)-heteroaryl, —O(CR⁴R⁵)_(m)-heterocyclyl or—NR⁴(CR⁴R⁵)_(m)-heterocyclyl, wherein any of said alkyl, alkenyl,alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,heterocyclyl and heterocyclylalkyl portions are optionally substitutedindependently with one or more groups independently selected from oxo(with the proviso that it is not substituted on an aryl or heteroaryl),halogen, cyano, nitro, trifluoromethyl, difluoromethoxy,trifluoromethoxy, azido, —NR⁴SO₂R⁶, —SO₂NR³R⁴, —C(O)R³, —C(O)OR³,—OC(O)R³, —NR⁴C(O)OR⁶, —NR⁴C(O)R³, —C(O)NR³R⁴, —NR³R⁴, —NR⁵C(O)NR³R⁴,—NR⁵C(NCN)NR³R⁴, —OR³, aryl, heteroaryl, arylalkyl, heteroarylalkyl,heterocyclyl and heterocyclylalkyl, and wherein said aryl, heteroaryl,arylalkyl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl rings areoptionally substituted independently with one or more groups selectedfrom halogen, hydroxyl, cyano, nitro, azido, fluoromethyl,difluoromethyl, trifluoromethyl, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄alkynyl, C₃-C₆ cycloalkyl, C₃-C₆ heterocycloalkyl, NR³R⁴ and OR³;

R⁷ is hydrogen, trifluoromethyl, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkylalkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl, whereinany of said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl portionsare optionally substituted independently with one or more groupsindependently selected from oxo (with the proviso that it is notsubstituted on an aryl or heteroaryl), halogen, cyano, nitro,trifluoromethyl, difluoromethyl, fluoromethyl, difluoromethoxy,trifluoromethoxy, azido, —NR¹¹SO₂R¹⁴, —SO₂NR¹¹R¹², —C(O)R¹¹, C(O)OR¹¹,—OC(O)R¹¹, —NR¹¹C(O)OR¹⁴, —NR¹¹C(O)R¹², —C(O)NR¹¹R¹², —SR¹¹, —S(O)R¹⁴,—SO₂R¹⁴, —NR¹¹R¹², —NR¹¹C(O)NR¹²R¹³, —NR¹¹C(NCN)NR¹²R¹³, —OR¹¹, C₁-C₁₀alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, aryl,heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl andheterocyclylalkyl, and wherein said aryl, heteroaryl, arylalkyl,heteroarylalkyl, heterocyclyl or heterocyclylalkyl rings are optionallysubstituted independently with one or more groups selected from halogen,hydroxyl, cyano, nitro, azido, fluoromethyl, difluoromethyl,trifluoromethyl, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₃-C₆cycloalkyl, C₃-C₆ heterocycloalkyl, NR³R⁴ and OR³;

R³ is hydrogen, trifluoromethyl, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkylalkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, phosphateor an amino acid residue, wherein any of said alkyl, alkenyl, alkynyl,cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyland heterocyclylalkyl portions are optionally substituted independentlywith one or more groups independently selected from oxo (with theproviso that it is not substituted on an aryl or heteroaryl), halogen,cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido,—NR¹¹SO₂R¹⁴, —SO₂NR¹¹R¹², —C(O)R¹¹, C(O)OR¹¹, —OC(O)R¹¹, —NR¹¹C(O)OR¹⁴,—NR¹¹C(O)R¹², —C(O)NR¹¹R¹², —SR¹¹, —S(O)R¹⁴, —SO₂R¹⁴, —NR¹¹R¹²,—NR¹¹C(O)NR¹²R¹³, —NR¹¹C(NCN)NR¹²R¹³, —OR¹¹, aryl, heteroaryl,arylalkyl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl,

or R³ and R⁴ together with the atom to which they are attached form a 4to 10 membered heteroaryl or heterocyclic ring, wherein said heteroaryland heterocyclic rings are optionally substituted independently with oneor more groups independently selected from halogen, cyano, nitro,trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, —NR¹¹SO₂R¹⁴,—SO₂NR¹¹R¹², —C(O)R¹¹, C(O)OR¹¹, —OC(O)R¹¹, —NR¹¹C(O)OR¹⁴, —NR¹¹C(O)R¹⁴,—C(O)NR¹¹R¹¹R¹², —SR¹¹, —S(O)R¹⁴, —SO₂R¹⁴, —NR¹¹R¹², —NR¹¹C(O)NR¹²R¹³,—NR¹¹C(NCN)NR¹²R¹³, —OR¹¹, aryl, heteroaryl, arylalkyl, heteroarylalkyl,heterocyclyl and heterocyclylalkyl:

R⁴ and R⁵ independently are hydrogen or C₁-C₆ alkyl, or

R⁴ and R⁵ together, with the atom to which they are attached form a 4 to10 membered carbocyclic ring, wherein said alkyl and carbocyclic ringare optionally substituted, independently with one or more groupsindependently selected from halogen, cyano, nitro, trifluoromethyl,difluoromethoxy, trifluoromethoxy, azido, —NR¹¹SO₂R¹⁴, —SO₂NR¹¹R¹²,—C(O)R¹¹, C(O)OR¹¹, —OC(O)R¹¹, —NR¹¹C(O)OR¹⁴, —NR¹¹C(O)R¹²,—C(O)NR¹¹R¹², —SR¹¹, —S(O)R¹⁴, —SO₂R¹⁴, —NR¹¹R¹², —NR¹¹C(O)NR¹²R¹³,—NR¹¹C(NCN)NR¹²R¹³, —OR¹¹, aryl, heteroaryl, arylalkyl, heteroarylalkyl,heterocyclyl, and heterocyclylalkyl:

R⁶ is trifluoromethyl, C₁-C₁₀ alkyl, C₃-C₁₀ cycloalkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl, whereinany of said alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, heterocyclyl and heterocyclylalkyl portions areoptionally substituted independently with one or more groupsindependently selected from oxo (with the proviso that it is notsubstituted on an aryl or heteroaryl), halogen, cyano, nitro,trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, —NR¹¹SO₂R¹⁴,—SO₂NR¹¹R¹², —C(O)R¹¹, C(O)OR¹¹, —OC(O)R¹¹, —NR¹¹C(O)OR¹⁴, —NR¹¹C(O)R¹²,—C(O)NR¹¹R¹², —SR¹¹, —S(O)R¹⁴, —SO₂R¹⁴, —NR¹¹R¹², —NR¹¹C(O)NR¹²R¹³,—NR¹¹C(NCN)NR¹²R¹³, —OR¹¹, aryl, heteroaryl, arylalkyl, heteroarylalkyl,heterocyclyl and heterocyclylalkyl;

wherein in Formulas I and V, R¹⁰ is hydrogen, hydroxy, halogen, cyano,nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, —SR¹¹,—OR³, —C(O)R³, —C(O)OR³, —NR⁴C(O)OR⁶, —OC(O)R³, —NR⁴SO₂R⁶, —SO₂NR³R⁴,—NR⁴C(O)R³, —C(O)NR³R⁴, —NR⁵C(O)NR³R⁴, —NR⁵C(NCN)NR³R⁴, —NR³R⁴, C₁-C₁₀alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀cycloalkylalkyl, —S(O)_(j)(C₁-C₆ alkyl), —S(O)_(j)(CR⁴R⁵)_(m)-aryl,aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl,heterocyclylalkyl, —O(CR⁴R⁵)_(m)-aryl, —NR⁴(CR⁴R⁵)_(m)-aryl,—O(CR⁴R⁵)_(m)-heteroaryl, —NR⁴(CR⁴R⁵)_(m)-heteroaryl,—O(CR⁴R⁵)_(m)-heterocyclyl or —NR⁴(CR⁴R⁵)_(m)-heterocyclyl, wherein anyof said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl portionsare optionally substituted independently with one or more groupsindependently selected from oxo (with the proviso that it is notsubstituted on an aryl or heteroaryl), halogen, cyano, nitro,trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, —NR⁴SO₂R⁶,—SO₂NR³R⁴, —C(O)R³, —C(O)OR³, —OC(O)R³, —NR⁴C(O)OR⁶, —NR⁴C(O)R³,—C(O)NR³R⁴, —NR³R⁴, —NR⁵C(O)NR³R⁴, —NR⁵C(NCN)NR³R⁴, —OR³, aryl,heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, andheterocyclylalkyl, and wherein said aryl, heteroaryl, arylalkyl,heteroarylalkyl, heterocyclyl or heterocyclylalkyl rings are optionallysubstituted independently with one or more groups selected from halogen,hydroxyl, cyano, nitro, azido, fluoromethyl, difluoromethyl,trifluoromethyl, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₃-C₆cycloalkyl, C₃-C₆ heterocycloalkyl, NR³R⁴ and OR³;

and wherein in Formulas II and Iv, each R¹⁰ is independently hydrogen,cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido,—C(O)R³, —C(O)OR³, —SO₂NR³R⁴, —C(O)NR³R⁴, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl,C₃-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkylalkyl,—S(O)_(j)(C₁-C₆ alkyl), —S(O)_(j)(CR⁴R⁵)_(m)-aryl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl, whereinany of said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkylportions, are optionally substituted independently with one or moregroups independently selected front oxo (with the proviso that it is notsubstituted on an aryl or heteroaryl), halogen, cyano, nitro,trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, —NR⁴SO₂R⁶,—SO₂NR³R⁴, —C(O)R³, —C(O)OR³, —OC(O)R³, —NR⁴C(O)OR⁶, —NR⁴C(O)R³,—C(O)NR³R⁴, —NR³R⁴, —NR⁵C(O)NR³R⁴, —NR⁵C(NCN)NR³R⁴, —OR³, aryl,heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl andheterocyclylalkyl, and wherein said aryl, heteroaryl, arylalkyl,heteroarylalkyl, heterocyclyl or heterocyclylalkyl rings are optionallysubstituted independently with one or more groups selected from halogen,hydroxyl, cyano, nitro, azido, fluoromethyl, difluoromethyl,trifluoromethyl, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₃-C₆cycloalkyl, C₃-C₆ heterocycloalkyl, NR³R⁴ and OR³;

R¹¹, R¹² and R¹³ independently are hydrogen, lower alkyl, lower alkenyl,aryl and arylalkyl, and R¹⁴ is lower alkyl, lower alkenyl, aryl andarylalkyl,

or any two of R¹¹, R¹², R¹³ and R¹⁴ together with the atom to which theyare attached form a 4 to 10 membered heteroaryl or heterocyclic ring,wherein said alkyl, alkenyl, aryl, arylalkyl, heteroaryl ring andheterocyclic ring are optionally substituted independently with one ormore groups independently selected from halogen, cyano, nitro,trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, aryl,heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, andheterocyclylalkyl;

W is heteroaryl, heterocyclyl, —C(O)OR³, —C(O)NR³R⁴, —C(O)NR⁴OR³,—C(O)R⁴OR³, —C(O)NR⁴SO₂R³, —C(O)(C₃-C₁₀ cycloalkyl), —C(O)(C₁-C₁₀alkyl), —C(O)(aryl), —C(O)(heteroaryl), —C(O)(heterocyclyl) or CR³R³wherein any of said heteroaryl, heterocyclyl, —C(O)OR³, —C(O)NR³R⁴,—C(O)NR⁴OR³, —C(O)R⁴OR³, —C(O)NR⁴SO₂R³, —C(O)(C₃-C₁₀ cycloalkyl),—C(O)(C₁-C₁₀ alkyl), —C(O)(aryl), —C(O)(heteroaryl), —C(O)(heterocyclyl)and CR³OR³ are optionally substituted independently with one or moregroups independently selected from halogen, cyano, nitro, azido, —NR³R⁴,—OR³, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, cycloalkyl andheterocycloalkyl, wherein any of said C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl,C₂-C₁₀ alkynyl, cycloalkyl and heterocycloalkyl are optionallysubstituted independently with 1 or more groups independently selectedfrom —NR³R⁴ and —OR³;

m is 0, 1, 2, 3, 4 or 5; and

j is 0, 1 or 2.

In a further aspect, the present invention provides compositions thatinhibit MEK comprising one or more compounds of Formulas I-V.

The invention also provides methods of making the compounds of FormulasI-V.

In a further aspect the present invention provides a method of using thecompounds of this invention as a medicament to treat diseases or medicalconditions mediated by MEK. For example, this invention provides amethod for treatment of a hyperproliferative disorder or an inflammatorycondition in a mammal comprising administrating to said mammal one ormore compounds of Formula I-V or a pharmaceutical acceptable sail orprodrug thereof in an amount effective to treat said hyperproliferativedisorder.

In a further aspect the present invention provides treating orpreventing an MEK-mediated condition, comprising administering to ahuman or animal in need thereof a pharmaceutical composition comprisinga compound of Formula I-V or a pharmaceutically-acceptable salt or invivo cleavable prodrug thereof in an amount effective to treat orprevent said MEK-mediated condition.

The inventive compounds may further be used advantageously incombination with other known therapeutic agents.

The invention also relates to pharmaceutical compositions that inhibitMEK, comprising an effective amount of a compound selected fromcompounds of Formulas I-V or pharmaceutically acceptable prodrugs,pharmaceutically active metabolites, or pharmaceutically acceptablesalts thereof.

An additional aspect of the invention is the use of a compound ofFormula I, Formula II, Formula III, Formula IV or Formula V in thepreparation of a medicament for the treatment or prevention of a diseaseor medical condition mediated by MEK in a warm-blooded animal;preferably a mammal, more preferably a human, suffering from suchdisorder. More particularly, the invention includes the use of acompound of the invention in the preparation of a medicament for thetreatment or prevention of a hyperproliferative disorder or aninflammatory condition in a mammal.

Additional advantages and novel features of this invention shall be setforth in part in the description that follows, and in part will becomeapparent to those skilled in the art upon examination of the followingspecification or may be learned by the practice of the invention. Theadvantages of the invention may be realized and attained by means of theinstrumentalities, combinations, compositions, and methods particularlypointed out in the appended claims.

BRIEF DESCRIPTION OF THE FIGURES

The accompanying drawings, which are incorporated herein and form a partof the specification, illustrate non-limiting embodiments of the presentinvention, and together with the description, serve to explain theprinciples of the invention.

In the Figures:

FIG. 1 shows a reaction scheme for the synthesis of compounds 5-7.

FIG. 2 shows a reaction scheme for the synthesis of compounds 7 and 11.

FIG. 3 shows a reaction scheme for the synthesis of compounds 14 and 15.

FIG. 4 shows a reaction scheme for the synthesis of compound 16.

FIG. 5 shows a reaction scheme for the synthesis of compounds 18-23.

FIG. 6 shows a reaction scheme for the synthesis of compounds 25-27.

FIG. 7 shows a reaction scheme for the synthesis of compound 33.

FIG. 8 shows a reaction scheme for the synthesis of compounds 34-36.

FIG. 9 shows a reaction scheme for the synthesis of compound 40.

FIG. 10 shows a reaction scheme for the synthesis of compounds 42-46.

FIG. 11 shows a reaction scheme for the synthesis of compound 47.

FIG. 12 shows a reaction scheme for the synthesis of compound 48.

FIG. 13 shows a reaction scheme for the synthesis of compound 49.

FIG. 14 shows a reaction scheme for the synthesis of compound 51.

FIG. 15 shows a reaction scheme for the synthesis of compounds 54-57.

FIG. 16 shows a reaction scheme for the synthesis of compounds 54 and56.

FIG. 17 shows a reaction scheme for an alternate synthesis of compounds54-57.

FIG. 18 shows a reaction scheme for the synthesis of compounds 54 and60.

FIG. 19 shows a reaction scheme for the synthesis of compounds 62-64.

FIG. 20 shows a reaction scheme for the synthesis of compound 63.

FIG. 21 shows a reaction scheme for the synthesis of compounds 61 and66.

FIG. 22 shows a reaction scheme for an alternate synthesis of compound61.

FIG. 23 shows a reaction scheme for the synthesis of compound 65.

FIG. 24 shows a reaction scheme for the synthesis of compounds 65 and70.

FIG. 25 shows a reaction scheme for an alternate synthesis of compound65.

FIG. 26 shows a reaction scheme for an alternate synthesis of compound65.

FIG. 27 shows a reaction scheme for an alternate synthesis of compound65.

FIG. 28 shows a reaction scheme for an alternate synthesis of compound61.

FIG. 29 shows a reaction scheme for the synthesis of compound 80.

FIG. 30 shows a reaction scheme for the synthesis of compounds 81 and82.

FIG. 31 shows a reaction scheme for the synthesis of compounds 83 and84.

FIG. 32 shows a reaction scheme for the synthesis of compound 85.

FIG. 33 shows a reaction scheme, for the synthesis of compounds 86-91.

FIG. 34 shows a reaction scheme for the synthesis of compounds 92 and93.

FIG. 35 shows a reaction scheme for the synthesis of compound 96.

FIG. 36 shows a reaction scheme for the synthesis of compounds 96, 100,101 and 102.

FIG. 37 shows a reaction scheme for the synthesis of compounds 109, 110and 111.

FIG. 38 shows an alternate reaction scheme for the synthesis ofcompounds 109, 110 and 111.

FIG. 39 shows a reaction scheme for the synthesis of compounds 119, 120and 121.

FIG. 40 shows a reaction scheme for the synthesis of compounds 124 and125.

FIG. 41 shows a reaction scheme for the synthesis of compounds 128, 129and 130.

DETAILED DESCRIPTION OF THE INVENTION

The inventive compounds of the Formulas I-v and tautomers, metabolites,resolved enantiomers, diastereomers, solvates and pharmaceuticallyacceptable salts and prodrugs thereof are useful in the treatment ofhyperproliferative diseases. In general, one aspect the presentinvention relates to compounds of Formula I-v that act as MEKinhibitors.

Specifically, one aspect of the invention relates to compounds havingthe general Formula I

and tautomers, pharmaceutically accepted salts, pharmaceuticallyacceptable prodrugs, metabolites, and solvates thereof, wherein:

X is N or CR¹⁰:

Y is NR³, O, S, S(O), S(O)₂, C(O) or CH₂;

R¹, R², R⁸, R⁹ and R¹⁰ are independently hydrogen, hydroxy, halogen,cyano, nitro, trifluoromethyl, difluoromethyl, fluoromethyl,fluoromethoxy, difluoromethoxy, trifluoromethoxy, azido, —SR¹¹, —OR³,—C(O)R³, —C(O)OR³, —NR⁴C(O)OR³, —OC(O)R³, —NR⁴SO₂R⁶, —SO₂NR³R⁴,—NR⁴C(O)R³, —C(O)NR³R⁴, —NR⁵C(O)NR³R⁴, —NR⁵C(NCN)NR³R⁴, —NR³R⁴, C₁-C₁₀alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₂-C₁₀ cycloalkyl, C₃-C₁₀cycloalkylalkyl, —S(O)_(j)(C₁-C₆ alkyl), —S(O)_(j)(CR⁴R⁵)_(m)-aryl,aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl,heterocyclylalkyl, —O(CR⁴R⁵)_(m)-aryl, —NR⁴(CR⁴R⁵)_(m)-aryl,—O(CR⁴R⁵)_(m)-heteroaryl, —NR⁴(CR⁴R⁵)_(m)-heteroaryl,—O(CR⁴R⁵)_(m)-heterocyclyl or —NR⁴(CR⁴R⁵)_(m)-heterocyclyl, wherein anyof said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl portionsare optionally substituted independently with one or more groupsindependently selected from oxo (with the proviso that it is notsubstituted on an aryl or heteroaryl), halogen, cyano, nitro,trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, —NR⁴SO₂R⁶,—SO₂NR³R⁴, —C(O)R³, —C(O)OR³, —OC(O)R³, —NR⁴C(O)OR⁶, —NR⁴C(O)R³,—C(O)NR³R⁴, —NR³R⁴, —NR⁵C(O)NR³R⁴, —NR⁵C(NCN)NR³R⁴, —OR³, aryl,heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, andheterocyclylalkyl, and wherein said aryl, heteroaryl, arylalkyl,heteroarylalkyl, heterocyclyl or heterocyclylalkyl rings are optionallysubstituted independently with one or more groups selected from halogen,hydroxyl, cyano, nitro, azido, fluoromethyl, difluoromethyl,trifluoromethyl, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₃-C₆cycloalkyl, C₃-C₆ heterocycloalkyl, NR³R⁴ and OR³;

R⁷ is hydrogen, trifluoromethyl, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkylalkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, heterocyclyl, or heterocyclylalkyl, whereinany of said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl portionsare optionally substituted independently with one or more groupsindependently selected from oxo (with the proviso that it is notsubstituted on an aryl or heteroaryl), halogen, cyano, nitro,trifluoromethyl, difluoromethyl, fluoromethyl, difluoromethoxy,trifluoromethoxy, azido, —NR¹¹SO₂R¹⁴, —SO₂NR¹¹R¹², —C(O)R¹¹, C(O)R¹¹,—OC(O)R¹¹, —NR¹¹C(O)OR¹⁴, —NR¹¹C(O)R¹², —C(O)NR¹¹R¹², —SR¹¹, —S(O)R¹⁴,—SO₂R¹⁴, —NR¹¹R¹², —NR¹¹C(O)NR¹²R¹³, —NR¹¹C(NCN)NR¹²R¹³, —OR¹¹, C₁-C₁₀alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, aryl,heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl andheterocyclylalkyl, and wherein said aryl, heteroaryl, arylalkyl,heteroarylalkyl, heterocyclyl and heterocyclylalkyl rings are optionallysubstituted independently with one or more groups selected from halogen,hydroxyl, cyano, nitro, azido, fluoromethyl, difluoromethyl,trifluoromethyl, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₃-C₆cycloalkyl, C₃-C₆ heterocycloalkyl, NR³R⁴ and OR³;

R³ is hydrogen, trifluoromethyl, C₃-C₁₀ alkyl, C₁-C₁₀ alkenyl, C₂-C₁₀alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkylalkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, phosphateor an amino acid residue, wherein any of said alkyl, alkenyl, alkynyl,cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyland heterocyclylalkyl portions are optionally substituted independentlywith one or more groups independently selected from oxo (with theproviso that it is not substituted on an aryl or heteroaryl), halogen,cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido,—NR¹¹SO₂R¹⁴, —SO₂NR¹¹R¹², —C(O)R¹¹, —C(O)OR¹¹, —OC(O)R¹¹, —NR¹¹C(O)OR¹⁴,—NR¹¹C(O)R¹², —C(O)NR¹¹R¹², —SR¹¹, —S(O)R¹⁴, —SO₂R¹⁴, —NR¹¹R¹²,—NR¹¹C(O)NR¹²R¹³, —NR¹¹C(NCN)NR¹²R¹³, —OR¹¹, aryl, heteroaryl,arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl.

or R³ and R⁴ together with the atom to which they are attached form a 4to 10 membered heteroaryl or heterocyclic ring, wherein said heteroaryland heterocyclic rings are optionally substituted independently with oneor more groups independently selected from halogen, cyano, nitro,trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, —NR¹¹SO₂R¹⁴,—SO₂NR¹¹R¹², —C(O)R¹¹, —C(O)OR¹¹, —OC(O)R¹¹, —NR¹¹C(O)OR¹⁴,—NR¹¹C(O)R¹², —C(O)NR¹¹R¹², —SR¹¹, —S(O)R¹⁴, —SO₂R¹⁴, —NR¹¹R¹²,—NR¹¹C(O)NR¹²R¹³, —NR¹¹C(NCN)NR¹²R¹³, —OR¹¹, aryl, heteroaryl,arylalkyl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl;

R⁴ and R⁵ independently are hydrogen or C₁-C₆ alkyl, or

R⁴ and R⁵ together with the atom to which they are attached form a 4 to10 membered carbocyclic ring, wherein said alkyl and said carbocyclicring are optionally substituted independently with one or more groupsindependently selected from halogen, cyano, nitro, trifluoromethyl,difluoromethoxy, trifluoromethoxy, azido, —NR¹¹SO₂R¹⁴, —SO₂NR¹¹R¹²,—C(O)R¹¹, —C(O)OR¹¹, —OC(O)R¹¹, —NR¹¹C(O)OR¹⁴, —NR¹¹C(O)R¹²,—C(O)NR¹¹R¹², —SR¹¹, —S(O)R¹⁴, —SO₂R¹⁴, —NR¹¹R¹², —NR¹¹C(O)NR¹²R¹³,—NR¹¹C(NCN)NR¹²R¹³, —OR¹¹, aryl, heteroaryl, arylalkyl, heteroarylalkyl,heterocyclyl and heterocyclylalkyl;

R⁶ is trifluoromethyl, C₁-C₁₀ alkyl, C₃-C₁₀ cycloalkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl, whereinany of said alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, heterocyclyl and heterocyclylalkyl portions areoptionally substituted independently with one or more groupsindependently selected from oxo (with the proviso that it is notsubstituted on an aryl or heteroaryl), halogen, cyano, nitro,trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, —NR¹¹SO₂R¹⁴,—SO₂NR¹¹R¹², —C(O)R¹¹, —C(O)OR¹¹, —OC(O)R¹¹, —NR¹¹C(O)OR¹⁴,—NR¹¹C(O)R¹², —C(O)NR¹¹R¹², —SR¹¹, —S(O)R¹⁴, —SO₂R¹⁴, —NR¹¹R¹²,—NR¹¹C(O)NR¹²R¹³,

—NR¹¹C(NCN)NR¹²R¹³, —OR¹¹, aryl, heteroaryl, arylalkyl, heteroarylalkyl,heterocyclyl and heterocyclylalkyl:

R¹¹, R¹² and R¹³ independently are hydrogen, lower alkyl, lower alkenyl,aryl and arylalkyl, and R¹⁴ is lower alkyl, lower alkenyl, aryl andarylalkyl,

or any two of R¹¹, R¹², R¹³ and R¹⁴ together with the atom to which theyare attached form a 4 to 10 membered heteroaryl or heterocyclic ring,wherein said alkyl, alkenyl, aryl, arylalkyl, heteroaryl ring andheterocyclic ring are optionally substituted independently with one ormore groups independently selected from halogen, cyano, nitro,trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, aryl,heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl andheterocyclylalkyl;

W is heteroaryl, heterocyclyl C(O)OR³, —C(O)NR³R⁴, —C(O)NR⁴OR³,—C(O)R⁴OR³, —C(O)NR⁴SO₂R³, —C(O)(C₃-C₁₀ cycloalkyl), —C(C₁-C₁₀ alkyl),—C(O)(aryl), —C(O)(heteroaryl), —C(O)(heterocyclyl) or —CR³OR³ whereinany of said heteroaryl, heterocyclyl, —C(O)OR³, —C(O)NR³R⁴, —C(O)NR⁴OR³,—C(O)R⁴OR³, —C(O)NR⁴SO₂R³, —C(O)(C₃-C₁₀ cycloalkyl), —C(O)(C₁-C₁₀alkyl), —C(O)(aryl), —C(O)(heteroaryl), —C(O)(heterocyclyl) and CR³OR³are optionally substituted independently with one or more groupsindependently selected from halogen, cyano, nitro, azido, —NR³R⁴, —OR³,C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, cycloalkyl andheterocycloalkyl, wherein any of said C₁-C₁₀ alkyl. C₂-C₁₀ alkenyl,C₂-C₁₀ alkynyl, cycloalkyl and heterocycloalkyl are optionallysubstituted independently with 1 or more groups independently selectedfrom —NR³R⁴ and —OR³;

m is 0, 1, 2, 3, 4 or 5; and

j is 0.1 or 2.

In one embodiment, X is N and Y is NH.

In another embodiment, W is selected from heteroaryl, —C(O)OR³,—C(O)NR³R⁴, —C(O)NR⁴OR³ and —C(O)NR⁴S(O)R³.

In yet another embodiment, W is selected from

In a further embodiment, W is selected from

FIGS. 1-3, 6, 7, 10-14 and 35-36 show non-limiting examples of thesynthesis of compounds of this invention having the general Formula I.

In addition to compounds of the general Formula I, this inventionfurther includes compounds of the general Formula II:

and tautomers, metabolites, resolved enantiomers, diastereomers,solvates and pharmaceutically acceptable salts and prodrugs thereof,wherein:

where R¹, R², R⁸ and R⁹ are independently hydrogen, halogen, cyano,nitro, trifluoromethyl, difluoromethyl, fluoromethyl, fluoromethoxy,difluoromethoxy, trifluoromethoxy, azido, —SR¹¹, —OR³, —C(O)R³,—C(O)OR³, —NR⁴C(O)OR⁶, —OC(O)R³, —NR⁴SO₂R⁶, —SO₂NR³R⁴, —NR⁴C(O)R³,—C(O)NR³R⁴, —NR⁵C(O)NR³R⁴, —NR⁵C(NCN)NR³R⁴, —NR³R⁴, C₁-C₁₀ alkyl, C₂-C₁₀alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkylalkyl,—S(O)_(j)(C₁-C₆ alkyl), —S(O)_(j)(CR⁴R⁵)_(m)-aryl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl,—O(CR⁴R⁵)_(m)-aryl, —NR⁴(CR⁴R⁵)_(m)-aryl, —O(CR⁴R⁵)_(m)-heteroaryl,—NR⁴(CR⁴R⁵)_(m)-heteroaryl, —O(CR⁴R⁵)_(m)-heterocyclyl or—NR⁴(CR⁴R⁵)_(m)-heterocyclyl, wherein any of said alkyl, alkenyl,alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,heterocyclyl and heterocyclylalkyl portions are optionally substitutedindependently with one or more groups independently selected from oxo(with the proviso that it is not substituted on an aryl or heteroaryl),halogen, cyano, nitro, trifluoromethyl, difluoromethoxy,trifluoromethoxy, azido, —NR⁴SO₂R⁶, —SO₂NR³R⁴, —C(O)R³, —C(O)OR³,—OC(O)R³, —NR⁴C(O)OR⁶, —NR⁴C(O)R³, —C(O)NR³R⁴, —NR³R⁴, —NR⁵C(O)NR³R⁴,—NR⁵C(NCN)NR³R⁴, —OR³, aryl, heteroaryl, arylalkyl, heteroarylalkyl,heterocyclyl, and heterocyclylalkyl, and wherein said aryl, heteroaryl,arylalkyl, heteroarylalkyl heterocyclyl and heterocyclylalkyl rings areoptionally substituted independently with one or more groups selectedfrom halogen, hydroxyl, cyano, nitro, azido, fluoromethyl,difluoromethyl, trifluoromethyl, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄alkynyl, C₃-C₆ cycloalkyl, C₃-C₆ heterocycloalkyl, NR³R⁴ and OR³;

R⁷ is hydrogen, trifluoromethyl, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkylalkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl, whereinany of said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl portionsare optionally substituted independently with one or more groupsindependently selected from oxo (with the proviso that it is notsubstituted on ah aryl or heteroaryl), halogen, cyano, nitro,trifluoromethyl, difluoromethyl, fluoromethyl, difluoromethoxy,trifluoromethoxy, azido, —NR¹¹SO₂R¹⁴, —SO₂NR¹¹R¹², —C(O)R¹¹, —C(O)OR¹¹,—OC(O)R¹¹, —NR¹¹C(O)OR¹⁴, —NR¹¹C(O)R¹⁴, —C(O)NR¹¹R¹², —SR¹¹, —S(O)R¹⁴,—SO₂R¹⁴, —NR¹¹R¹², —NR¹¹C(O)NR¹²R¹³, —NR¹¹C(NCN)NR¹²R¹³, —OR¹¹, C₁-C₁₀alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, aryl,heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl andheterocyclylalkyl, and wherein said aryl, heteroaryl, arylalkyl,heteroarylalkyl, heterocyclyl and heterocyclylalkyl rings are optionallysubstituted independently with one or more groups selected from halogen,hydroxyl, cyano, nitro, azido, fluoromethyl, difluoromethyl,trifluoromethyl, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₃-C₆cycloalkyl, C₃-C₆ heterocycloalkyl, NR³R⁴ and OR³;

each R¹⁰ is independently hydrogen, cyano, nitro, trifluoromethyl,difluoromethoxy, trifluoromethoxy, azido, —C(O)R³, —C(O)OR³, —SO₂NR³R⁴,—C(O)NR³R⁴, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀cycloalkyl, C₃-C₁₀ cycloalkylalkyl, S(O)_(j)(C₁-C₆ alkyl),—S(O)_(j)(CR⁴R⁵)_(m)-aryl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,heterocyclyl or heterocyclylalkyl, wherein any of said alkyl, alkenyl,alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,heterocyclyl and heterocyclylalkyl portions are optionally substitutedindependently with one or more groups independently selected from oxo(with the proviso that it is not substituted on an aryl or heteroaryl),halogen, cyano, nitro, trifluoromethyl, difluoromethoxy,trifluoromethoxy, azido, —NR⁴SO₂R⁶, —SO₂NR³R⁴, —C(O)R³, —C(O)OR³,—OC(O)R³, —NR⁴C(O)OR⁶, —NR⁴C(O)R³, —C(O)NR³R⁴, —NR³R⁴, —NR⁵C(O)NR³R⁴,—NR⁵C(NCN)NR³R³, —OR³, aryl, heteroaryl, arylalkyl, heteroarylalkyl,heterocyclyl, and heterocyclylalkyl, and wherein said aryl, heteroaryl,arylalkyl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl rings areoptionally substituted independently with one or more groups selectedfrom halogen, hydroxyl, cyano, nitro, azido, fluoromethyl,difluoromethyl, trifluoromethyl, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄alkynyl, C₃-C₆ cycloalkyl, C₃-C₆, heterocycloalkyl. NR³R⁴ and OR³;

R³ is hydrogen, trifluoromethyl, C₁-C₁₀ alkyl, C₃-C₁₀ alkenyl, C₂-C₁₀alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkylalkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, phosphateor an amino acid residue, wherein any of said alkyl, alkenyl, alkynyl,cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyland heterocyclylalkyl portions are optionally substituted independentlywith one or more groups independently selected from oxo (with theproviso that it is not substituted on an aryl or heteroaryl), halogen,cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido,—NR¹¹SO₂R¹⁴, —SO₂NR¹¹R¹², —C(O)R¹¹, —C(O)OR¹¹, —OC(O)R¹¹, —NR¹¹C(O)OR¹⁴,—NR¹¹C(O)R₁₂, —C(O)NR¹¹R¹², —SR¹¹, —S(O)R¹⁴, —SO₂R¹⁴, —NR¹¹R¹²,—NR¹¹C(O)NR¹²R¹³, —NR¹¹C(NCN)NR¹²R¹³, —OR¹¹, aryl, heteroaryl,arylalkyl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl,

or R³ and R⁴ together with the atom to which they are attached form a 4to 10 membered heteroaryl or heterocyclic ring, wherein said heteroaryland heterocyclic rings are optionally substituted independently with oneor more groups independently selected from halogen, cyano, nitro,trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, —NR¹¹SO₂R¹⁴,—SO₂NR¹¹R¹², —C(O)R¹¹, —C(O)OR¹¹, —OC(O)R¹¹, —NR¹¹C(O)OR¹⁴,—NR¹¹C(O)R¹², —C(O)NR¹¹R¹², —SR¹¹, —S(O)R¹⁴, —SO₂R¹⁴, —NR¹¹R¹²,—NR¹¹C(O)NR¹²R¹³, —NR¹¹C(NCN)NR¹²R¹³, —OR¹¹, aryl, heteroaryl,arylalkyl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl:

R⁴ and R⁵ independently are hydrogen or C₁-C₆ alkyl, or

R⁴ and R⁵ together with the atom to which they are attached form a 4 to10 membered carbocyclic ring, wherein said alkyl and carbocyclic ringare optionally substituted independently with one or more groupsindependently selected from halogen, cyano, nitro, trifluoromethyl,difluoromethoxy, trifluoromethoxy, azido, —NR¹¹SO₂R¹⁴, —SO₂NR¹¹R¹²,—C(O)R¹¹, —C(O)OR¹¹, —OC(O)R¹¹, —NR¹¹C(O)OR¹⁴, —NR¹¹C(O)R¹²,—C(O)NR¹¹R¹², —SR¹¹, —S(O)R¹⁴, —SO_(29l R) ¹⁴, —NR¹¹R¹²,—NR¹¹C(O)NR¹²R¹³, —NR¹¹C(NCN)NR¹²R¹³, —OR¹¹, aryl, heteroaryl,arylalkyl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl:

R⁶ is trifluoromethyl, C₁-C₁₀ alkyl, C₃-C₁₀ cycloalkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl, whereinany of said alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, heterocyclyl and heterocyclylalkyl portions areoptionally substituted independently with one or more groupsindependently selected from oxo (with the proviso that it is notsubstituted on an aryl or heteroaryl), halogen, cyano, nitro,trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, —NR¹¹SO₂R¹⁴,—SO₂NR¹¹R¹², —C(O)R¹¹, —C(O)OR¹¹, —OC(O)R¹¹, —NR¹¹C(O)OR¹⁴,—NR¹¹C(O)R¹², —C(O)NR¹¹R¹², —SR¹¹, —S(O)R¹⁴, —SO₂R¹⁴, —NR¹¹R¹²,—NR¹¹C(O)NR¹²R¹³, —NR¹¹C(NCN)NR¹²R¹³, —OR¹¹, aryl, heteroaryl,arylalkyl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl;

R¹¹, R¹² and R¹³ independently are hydrogen, lower alkyl, lower alkenyl,aryl and arylalkyl, and R¹⁴ is lower alkyl, lower alkenyl, aryl andarylalkyl.

or any two of R¹¹, R¹², R¹³ and R¹⁴ together with the atom to which theyare attached form a 4 to 10 membered heteroaryl or heterocyclic ring,wherein said alkyl, alkenyl, aryl, arylalkyl, heteroaryl ring andheterocyclic ring are optionally substituted independently with one ormore groups independently selected from halogen, cyano, nitro,trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, aryl,heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl andheterocyclylalkyl;

m is 0, 1, 2, 3, 4 or 5;

n is 1 or 2; and

j is 0, 1 or 2.

FIG. 5 shows non-limiting examples of the synthesis of compounds of thisinvention having the general Formula II.

In another embodiment, this invention relates to compounds of thegeneral Formula III

and tautomers, metabolites, resolved enantiomers, diastereomers,solvates and pharmaceutically acceptable salts and prodrugs thereof,wherein:

R¹, R², R⁸ and each R⁹ are independently hydrogen, halogen, cyano,nitro, trifluoromethyl, difluoromethyl, fluoromethyl, fluoromethoxy,difluoromethoxy, trifluoromethoxy, azido, —SR¹¹, —OR³, —C(O)R³,—C(O)OR³, —NR⁴C(O)OR⁶, —OC(O)R³, —NR⁴SO₂R⁶, —SO₂NR³R⁴, —NR⁴C(O)R³,—C(O)NR³R⁴, —NR⁵C(O)NR³R⁴, —NR⁵C(NCN)NR³R⁴, —NR³R⁴, C₁-C₁₀ alkyl, C₂-C₁₀alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkylalkyl,—S(O)_(j)(C₁-C₆ (alkyl), —S(O)_(j)(CR⁴R⁵)_(m)-aryl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl,—O(CR⁴R⁵)_(m)-aryl, —NR⁴(CR⁴R⁵)_(m)-aryl, —O(CR⁴R⁵)_(m)-heteroaryl,—NR⁴(CR⁴R⁵)_(m)-heteroaryl, —O(CR⁴R⁵)_(m)-heterocyclyl or—NR⁴(CR⁴R⁵)_(m)-heterocyclyl, wherein any of said alkyl, alkenyl,alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,heterocyclyl and heterocyclylalkyl portions are optionally substitutedindependently with one or more groups independently selected from oxo(with the proviso that it is not substituted on an aryl or heteroaryl),halogen, cyano, nitro, trifluoromethyl, difluoromethoxy,trifluoromethoxy, azido, —NR⁴SO₂R⁶, —SO₂NR³R⁴, —C(O)R³, —C(O)OR³,—OC(O)R³, —NR⁴C(O)OR⁶, —NR⁴C(O)R³, —C(O)NR³R⁴, —NR³R⁴, —NR⁵C(O)NR³R⁴,—NR⁵C(NCN)NR³R⁴, —OR³, aryl, heteroaryl, arylalkyl, heteroarylalkyl,heterocyclyl and heterocyclylalkyl, and wherein said aryl, heteroaryl,arylalkyl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl rings areoptionally substituted independently with one or more groups selectedfrom halogen, hydroxyl, cyano, nitro, azido, fluoromethyl,difluoromethyl, trifluoromethyl, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄alkynyl, C₃-C₆ cycloalkyl, C₃-C₆ heterocycloalkyl, NR³R⁴ and OR³;

R⁷ is hydrogen, trifluoromethyl, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkylalkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl, whereinany of said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl portionsare optionally substituted independently with one or more groupsindependently selected from oxo (with the proviso that it is notsubstituted on an aryl or heteroaryl), halogen, cyano, nitro,trifluoromethyl, difluoromethyl, fluoromethyl, difluoromethoxy,trifluoromethoxy, azido, —NR¹¹SO₂R¹⁴, —SO₂NR¹¹R¹², C(O)R¹¹, C(O)OR¹¹,—OC(O)R¹¹, —NR¹¹C(O)OR¹⁴, —NR¹¹C(O)R¹², —C(O)NR¹¹R¹², —SR¹¹, —S(O)R¹⁴,—SO₂R¹⁴, —NR¹¹R¹², —NR¹¹C(O)NR¹²R¹³, —NR¹¹C(NCN)NR¹²R¹³, —OR¹¹, C₁-C₁₀alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, aryl,heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl andheterocyclylalkyl, and wherein said aryl, heteroaryl, arylalkyl,heteroarylalkyl, heterocyclyl or heterocyclylalkyl rings are optionallysubstituted independently with one or more groups selected from halogen,hydroxyl, cyano, nitro, azido, fluoromethyl, difluoromethyl,trifluoromethyl, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₃-C₆cycloalkyl, C₃-C₆ heterocycloalkyl, NR³R⁴ and OR³;

R³ is hydrogen, trifluoromethyl, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkylalkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, phosphateor an amino acid residue, wherein any of said alkyl, alkenyl, alkynyl,cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyland heterocyclylalkyl portions are optionally substituted independentlywith one or more groups independently selected from oxo (with theproviso that it is not substituted on an aryl or heteroaryl), halogen,cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido,—NR¹¹SO₂R¹⁴, —SO₂NR¹¹R¹², —C(O)R¹¹, C(O)OR¹¹, —OC(O)R¹¹, —NR¹¹C(O)OR¹⁴,—NR¹¹C(O)R¹², —C(O)NR¹¹R¹², —SR¹¹, —S(O)R¹⁴, —SO₂R¹⁴, —NR¹¹R¹²,—NR¹¹C(O)NR¹²R¹³, —NR¹¹C(NCN)NR¹²R¹³, —OR¹¹, aryl, heteroaryl,arylalkyl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl,

or R³ and R⁴ together with the atom to which they are attached forth a 4to 10 membered heteroaryl and heterocyclic ring, wherein said heteroaryland heterocyclic rings are optionally substituted independently with oneor more groups independently selected from halogen, cyano, nitro,trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, —NR¹¹SO₂R¹⁴,—SO₂NR¹¹R¹², —C(O)R¹¹, C(O)OR¹¹, —OC(O)R¹¹, —NR¹¹C(O)OR¹⁴, —NR¹¹C(O)R¹²,—C(O)NR¹¹R¹², —SR¹¹, —S(O)R¹⁴, —SO₂R¹⁴, —NR¹¹R¹², —NR¹¹C(O)NR¹²R¹³,—NR¹¹C(NCN)NR¹²R¹³, —OR¹¹, aryl, heteroaryl, arylalkyl, heteroarylalkyl,heterocyclyl and heterocyclylalkyl;

R⁴ and R⁵ independently are hydrogen or C₁-C₆ alkyl, or

R⁴ and R⁵ together with the atom to which they are attached form a 4 to10 membered carbocyclic ring, wherein said alkyl and carbocyclic ringare optionally substituted independently with one or more groupsindependently selected from halogen, cyano, nitro, trifluoromethyl,difluoromethoxy, trifluoromethoxy, azido, —NR¹¹SO₂R¹⁴, —SO₂NR¹¹R¹²,—C(O)R¹¹, C(O)OR¹¹, —OC(O)R¹¹, —NR¹¹C(O)OR¹⁴, —NR¹¹C(O)R¹²,—C(O)NR¹¹R¹², —SR¹¹, —S(O)R¹⁴, —SO₂R¹⁴, —NR¹¹R¹², —NR¹¹C(O)NR¹²R¹¹,—NR¹¹C(NCN)NR¹²R¹³, —OR¹¹, aryl, heteroaryl, arylalkyl, heteroarylalkyl,heterocyclyl and heterocyclylalkyl;

R⁶ is trifluoromethyl, C₁-C₁₀ alkyl, C₃-C₁₀ cycloalkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl, whereinany of said alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, heterocyclyl and heterocyclylalkyl portions areoptionally substituted independently with one or more groupsindependently selected from oxo (with the proviso that it is notsubstituted on an aryl or heteroaryl), halogen, cyano, nitro,trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, —NR¹¹SO₂R¹⁴,—SO₂NR¹¹R¹², —C(O)R¹¹, C(O)OR¹¹, —OC(O)R¹¹, —NR¹¹C(O)OR¹⁴, —NR¹¹C(O)R¹²,—C(O)NR¹¹R¹², —SR¹¹, —S(O)R¹⁴, —SO₂R¹⁴, —NR¹¹R¹², —NR¹¹C(O)NR¹²R¹³,—NR¹¹C(NCN)NR¹²R¹³, —OR¹¹, aryl, heteroaryl, arylalkyl, heteroarylalkyl,heterocyclyl and heterocyclylalkyl;

R¹¹, R¹² and R¹³ independently are hydrogen, lower alkyl, lower alkenyl,aryl and arylalkyl, and

R¹⁴ is lower alkyl, lower alkenyl, aryl and arylalkyl:

or any two of R¹¹, R¹², R¹³ and R¹⁴ together with die atom to which theyare attached form a 4 to 10 membered heteroaryl or heterocyclic ring,wherein said alkyl, alkenyl, aryl, arylalkyl, heteroaryl ring andheterocyclic ring are optionally substituted independently with one ormore groups independently selected from halogen, cyano, nitro,trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, aryl,heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl andheterocyclylalkyl;

m is 0.1, 2, 3, 4 or 5; and

j is 0, 1 or 2.

FIGS. 8 and 9 show non-limiting examples of the synthesis of compoundsof this invention having the general Formula III.

In another embodiment, this invention relates to compounds of thegeneral Formula IV

and tautomers, metabolites, resolved enantiomers, diastereomers,solvates and pharmaceutically acceptable salts and prodrugs thereof,wherein:

R¹, R², R⁵ and R⁹ are independently hydrogen, halogen, cyano, nitro,trifluoromethyl, difluoromethyl, fluoromethyl, fluoromethoxy,difluoromethoxy, trifluoromethoxy, azido, —SR¹¹, —OR³, —C(O)R³,—C(O)OR³, —NR⁴C(O)OR⁶, —OC(O)R³, —NR⁴SO₂R⁶, —SO₂NR³R⁴, —NR⁴C(O)R³,—C(O)NR³R⁴, —NR⁵C(O)NR³R⁴, —NR⁵C(NCN)NR³R⁴, —NR³R⁴, C₁-C₁₀ alkyl, C₂-C₁₀alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkylalkyl,—S(O)_(j)(C₁-C₆ alkyl), —S(O)_(j)(CR⁴R⁵)_(m)-aryl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl,—O(CR⁴R⁵)_(m)-aryl, —NR⁴(CR⁴R⁵)_(m)-aryl, —O(CR⁴R⁵)_(m)-heteroaryl,—NR⁴(CR⁴R⁵)_(m)-heteroaryl, —O(CR⁴R⁵)_(m)-heterocyclyl or—NR⁴(CR⁴R⁵)_(m)-heterocyclyl, wherein any of said alkyl, alkenyl,alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,heterocyclyl and heterocyclylalkyl portions are optionally substitutedindependently with one or more groups independently selected from oxo(with the proviso that it is not substituted on an aryl or heteroaryl),halogen, cyano, nitro, trifluoromethyl, difluoromethoxy,trifluoromethoxy, azido, —NR⁴SO₂R⁶, —SO₂NR³R⁴, —C(O)R³, —C(O)OR³,—OC(O)R³, —NR⁴C(O)OR⁶, —NR⁴C(O)R⁴, —C(O)NR³R⁴, —NR³R⁴, —NR⁵C(O)NR³R⁴,—NR⁵C(NCN)NR³R⁴, —OR³, aryl, heteroaryl, arylalkyl, heteroarylalkyl,heterocyclyl, and heterocyclylalkyl, and wherein said aryl, heteroaryl,arylalkyl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl rings areoptionally substituted independently with one or more groups selectedfrom halogen, hydroxyl, cyano, nitro, azido, fluoromethyl,difluoromethyl, trifluoromethyl, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄alkynyl, C₃-C₆, cycloalkyl, C₃-C₆ heterocycloalkyl, NR³R⁴ and OR³;

each R⁷ is hydrogen, trifluoromethyl, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl,C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkylalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, orheterocyclylalkyl, wherein any of said alkyl, alkenyl, alkynyl,cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyland heterocyclylalkyl portions are optionally substituted independentlywith one or more groups independently selected from oxo (with theproviso that it is not substituted on an aryl or heteroaryl), halogen,cyano, nitro, trifluoromethyl, difluoromethyl, fluoromethyl,difluoromethoxy, trifluoromethoxy, azido, —NR¹¹SO₂R¹⁴, —SO₂NR¹¹R¹²,—C(O)R¹¹, C(O)OR¹¹, —OC(O)R¹¹, —NR¹¹C(O)OR¹⁴, —NR¹¹C(O)R¹²,—C(O)NR¹¹R¹², —SR¹¹, —S(O)R¹⁴, —SO₂R¹⁴, —NR¹¹R¹², —NR¹¹C(O)NR¹²R¹³,—NR¹¹C(NCN)NR¹²R¹³, —OR¹¹, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl,C₃-C₁₀ cycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl,heterocyclyl and heterocyclylalkyl, and wherein said aryl, heteroaryl,arylalkyl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl rings areoptionally substituted independently with one or more groups selectedfrom halogen, hydroxyl, cyano, nitro, azido, fluoromethyl,difluoromethyl, trifluoromethyl, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄alkynyl, C₃-C₆ cycloalkyl, C₃-C₆ heterocycloalkyl, NR²R⁴ and OR³;

each R¹⁰ is independently hydrogen, cyano, nitro, trifluoromethyl,difluoromethoxy, trifluoromethoxy, azido, —C(O)R³, —C(O)OR³, —SO₂NR³R⁴,—C(O)NR³R⁴, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀cycloalkyl, C₃-C₁₀ cycloalkylalkyl, —S(O)_(j)(C₁-C₆ alkyl),—S(O)_(j)(CR⁴R⁵)_(m)-aryl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,heterocyclyl or heterocyclylalkyl, wherein any of said alkyl, alkenyl,alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,heterocyclyl and heterocyclylalkyl portions are optionally substitutedindependently with one or more groups independently selected from oxo(with the proviso that it is not substituted on an aryl or heteroaryl),halogen, cyano, nitro, trifluoromethyl, difluoromethoxy,trifluoromethoxy, azido, —NR⁴SO₂R⁶, —SO₂NR³R⁴, —C(O)R³, —C(O)OR³,—OC(O)R³, —NR⁴C(O)OR⁶, —NR⁴C(O)R³, —C(O)NR³R⁴, —NR³R⁴, —NR⁵C(O)NR³R⁴,—NR⁵C(NCN)NR³R⁴, —OR³, aryl, heteroaryl, arylalkyl, heteroarylalkyl,heterocyclyl and heterocyclylalkyl, and wherein said aryl, heteroaryl,arylalkyl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl rings areoptionally substituted independently with one or more groups selectedfrom halogen, hydroxyl, cyano, nitro, azido, fluoromethyl,difluoromethyl, trifluoromethyl, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄alkynyl, C₃-C₆ cycloalkyl, C₃-C₆, heterocycloalkyl, NR³R⁴ and OR³;

R³ is hydrogen, trifluoromethyl, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkylalkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, phosphateor an amino acid residue, wherein any of said alkyl, alkenyl, alkynyl,cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyland heterocyclylalkyl portions are optionally substituted independentlywith one or more groups independently selected from oxo (with theproviso that it is not substituted on an aryl or heteroaryl), halogen,cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido,—NR¹¹SO₂R¹⁴, —SO₂NR¹¹R¹², —C(O)R¹¹, C(O)OR¹¹, —OC(O)R¹¹, —NR¹¹C(O)OR¹⁴,—NR¹¹C(O)R¹², —C(O)NR¹¹R¹², —SR¹¹, —S(O)R¹⁴, —SO₂R¹⁴, —NR¹¹R¹²,—NR¹¹C(O)NR¹²R¹³, —NR¹¹C(NCN)NR¹²R¹³, —OR¹¹, aryl, heteroaryl,arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl.

or R³ and R⁴ together with the atom to which they are attached form a 4to 10 membered heteroaryl or heterocyclic ring, wherein said heteroaryland heterocyclic rings are optionally substituted independently with oneor more groups independently selected from halogen, cyano, nitro,trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, —NR¹¹SO₂R¹⁴,—SO₂NR¹¹R¹², —C(O)R¹¹, —C(O)OR¹¹, —OC(O)R¹¹, —NR¹¹C(O)OR¹⁴,—NR¹¹C(O)R¹², —C(O)NR¹¹R¹², —SR¹¹, —S(O)R¹⁴, —SO₂R¹⁴, —NR¹¹R¹²,—NR¹¹C(O)NR¹²R¹³, —NR¹¹C(NCN)NR¹²R¹³, —OR¹¹, aryl, heteroaryl,arylalkyl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl;

R⁴ and R⁵ independently are hydrogen or C₁-C₆ alkyl, or

R⁴ and R⁵ together with the atom to which they are attached form a 4 to10 membered carbocyclic ring, wherein said alkyl and carbocyclic ringare optionally substituted independently with one or more groupsindependently selected from halogen, cyano, nitro, trifluoromethyl,difluoromethoxy, trifluoromethoxy, azido, —NR¹¹SO₂R¹⁴, —SO₂NR¹¹R¹²,—C(O)R¹¹, —C(O)OR¹¹, —OC(O)R¹¹, —NR¹¹C(O)OR¹⁴, —NR¹¹C(O)R¹²,—C(O)NR¹¹R¹², —SR¹¹, —S(O)R¹⁴, —SO₂R¹⁴, —NR¹¹R¹², —NR¹¹C(O)NR¹²R¹³,—NR¹¹C(NCN)NR¹²R¹¹, —OR¹¹, aryl, heteroaryl, arylalkyl, heteroarylalkyl,heterocyclyl and heterocyclylalkyl;

R⁶ is trifluoromethyl, C₁-C₁₀ alkyl, C₃-C₁₀ cycloalkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl, whereinany of said alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, heterocyclyl and heterocyclylalkyl portions areoptionally substituted independently with one or more groupsindependently selected from oxo (with the proviso that it is notsubstituted on an aryl or heteroaryl), halogen, cyano, nitro,trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, —NR¹¹SO₂R¹⁴,—SO₂NR¹¹R¹², —C(O)R¹¹, —C(O)OR¹¹, —OC(O)R¹¹, —NR¹¹C(O)OR¹⁴,—NR¹¹C(O)R¹², —C(O)NR¹¹R¹², —SR¹¹, —S(O)R¹⁴, —SO₂R¹⁴, —NR¹¹R¹²,—NR¹¹C(O)NR¹²R¹³, —NR¹¹C(NCN)NR¹²R¹³, —OR¹¹, aryl, heteroaryl,arylalkyl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl;

R¹¹, R¹² and R¹³ independently are hydrogen, lower alkyl, lower alkenyl,aryl and arylalkyl, and

R¹⁴ is lower alkyl, lower alkenyl, aryl and arylalkyl,

or any two of R¹¹, R¹², R¹³ and R¹⁴ together with the atom to which theyare attached form a 4 to 10 membered heteroaryl or heterocyclic ring,wherein said alkyl, alkenyl, aryl, arylalkyl, heteroaryl ring andheterocyclic ring are optionally substituted independently with one ormore groups independently selected from halogen, cyano, nitro,trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, aryl,heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl andheterocyclylalkyl;

m is 0, 1, 2, 3, 4 or 5; and

j is 0, 1 or 2.

FIG. 5 shows non-limiting examples of the synthesis of compounds of thisinvention having the general Formula IV.

In another embodiment, this invention relates to compounds of thegeneral Formula V

and tautomers, metabolites, resolved enantiomers, diastereomers,solvates and pharmaceutically acceptable salts and prodrugs thereof,wherein:

X is N or CR¹⁰;

R¹, R², R⁸, R⁹ and R¹⁰ are independently hydrogen, halogen, cyano,nitro, trifluoromethyl, difluoromethyl, fluoromethyl, fluoromethoxy,difluoromethoxy, trifluoromethoxy, azido, —SR¹¹, —OR³, —C(O)R³,—C(O)OR³, —NR⁴C(O)OR⁶, —OC(O)R³, —NR⁴SO₂R⁶, —SO₂NR³R⁴, —NR⁴C(O)R³,—C(O)NR³R⁴, —NR⁵C(O)NR³R⁴, —NR⁵C(NCN)NR³R⁴, —NR³R⁴, C₁-C₁₀ alkyl, C₂-C₁₀alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkylalkyl,—S(O)_(j)(C₁-C₆ alkyl), —S(O)_(j)(CR⁴R⁵)_(m)-aryl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl,—O(CR⁴R⁵)_(m)-aryl, —NR⁴(CR⁴R⁵)_(m)-aryl, —O(CR⁴R⁵)_(m)-heteroaryl,—NR⁴(CR⁴R⁵)_(m)-heteroaryl, —O(CR⁴R⁵)_(m)-heterocyclyl or—NR⁴(CR⁴R⁵)_(m)-heterocyclyl, wherein any of said alkyl, alkenyl,alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,heterocyclyl and heterocyclylalkyl portions are optionally substitutedindependently with one or more groups independently selected from oxo(with the proviso that it is not substituted on an aryl or heteroaryl),halogen, cyano, nitro, trifluoromethyl, difluoromethoxy,trifluoromethoxy, azido, —NR⁴SO₂R⁶, —SO₂NR³R⁴, —C(O)R³, —C(O)OR³,—OC(O)R³, —NR⁴C(O)OR⁶, —NR⁴C(O)R³, —C(O)NR³R⁴, —NR³R⁴, —NR⁵C(O)NR³R⁴,—NR⁵C(NCN)NR³R⁴, —OR³, aryl, heteroaryl, arylalkyl, heteroarylalkyl,heterocyclyl and heterocyclylalkyl, and wherein said aryl, heteroaryl,arylalkyl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl rings areoptionally substituted independently with one or more groups selectedfrom halogen, hydroxyl, cyano, nitro, azido, fluoromethyl,difluoromethyl, trifluoromethyl, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄alkynyl, C₃-C₆ cycloalkyl, C₃-C₆ heterocycloalkyl, NR³R⁴ and OR³;

R⁷ is hydrogen, trifluoromethyl, C₁-C₁₀ alkyl, C₁-C₁₀ alkenyl, C₂-C₁₀alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkylalkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl, whereinany of said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl portionsare optionally substituted independently with one or more groupsindependently selected from oxo (with the proviso that it is notsubstituted on an aryl or heteroaryl), halogen, cyano, nitro,trifluoromethyl, difluoromethyl, fluoromethyl, difluoromethoxy,trifluoromethoxy, azido, —NR¹¹SO₂R¹⁴, —SO₂NR¹¹R¹², —C(O)R¹¹, —C(O)OR¹¹,—OC(O)R¹¹, —NR¹¹C(O)OR¹⁴, —NR¹¹C(O)R¹², —C(O)NR¹¹R¹², —SR¹¹, —S(O)R¹⁴,—SO₂R¹⁴, —NR¹¹R¹², —NR¹¹C(O)NR¹²R¹³, —NR¹¹C(NCN)NR¹²R¹³, —OR¹¹, C₁-C₁₀alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, aryl,heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl andheterocyclylalkyl, and wherein said aryl, heteroaryl, arylalkyl,heteroarylalkyl, heterocyclyl and heterocyclylalkyl rings are optionallysubstituted independently with one or more groups selected from halogen,hydroxyl, cyano, nitro, azido, fluoromethyl, difluoromethyl,trifluoromethyl, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₃-C₆cycloalkyl, C₃-C₆ heterocycloalkyl, NR³R⁴ and OR³;

R³ is hydrogen, trifluoromethyl, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkylalkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, phosphateor an amino acid residue, wherein any of said alkyl, alkenyl, alkynyl,cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyland heterocyclylalkyl portions are optionally substituted independentlywith one or more groups independently selected from oxo (with theproviso that it is not substituted on an aryl or heteroaryl), halogen,cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido,—NR¹¹SO₂R¹⁴, —SO₂NR¹¹R¹², —C(O)R¹¹, C(O)OR¹¹, —OC(O)R¹¹, —NR¹¹C(O)OR¹⁴,—NR¹¹C(O)R¹², —C(O)NR¹¹R¹², —SR¹¹, —S(O)R¹⁴, —SO₂R¹⁴, —NR¹¹R¹²,—NR¹¹C(O)NR¹²R¹³, —NR¹¹C(NCN)NR¹²R¹³, —OR¹¹, aryl, heteroaryl,arylalkyl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl.

or R³ and R⁴ together with the atom to which they are attached form a 4to 10 membered heteroaryl and heterocyclic ring, wherein said heteroaryland heterocyclic rings are optionally substituted independently with oneor more groups independently selected from halogen, cyano, nitro,trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, —NR¹¹SO₂R¹⁴,—SO₂NR¹¹R¹², —C(O)R¹¹, C(O)OR¹¹, —OC(O)R¹¹, —NR¹¹C(O)OR¹⁴, —NR¹¹C(O)R¹²,—C(O)NR¹¹R¹², —SR¹¹, —S(O)R¹⁴, —SO₂R¹⁴, —NR¹¹R¹², —NR¹¹C(O)NR¹²R¹³,—NR¹¹C(NCN)NR¹²R¹³, —OR¹¹, aryl, heteroaryl, arylalkyl, heteroarylalkylheterocyclyl and heterocyclylalkyl;

R⁴ and R⁵ independently are hydrogen or C₁-C₆ alkyl, or

R⁴ and R⁵ together with the atom to which they are attached form a 4 to10 membered carbocyclic ring, wherein said alkyl and carbocyclic ringare optionally substituted independently with one or more groupsindependently selected from halogen, cyano, nitro, trifluoromethyl,difluoromethoxy, trifluoromethoxy, azido, —NR¹¹SO₂R¹⁴, —SO₂NR¹¹R¹²,—C(O)R¹¹, —C(O)OR¹¹, —OC(O)R¹¹, —NR¹¹C(O)OR¹⁴, —NR¹¹C(O)R¹²,—C(O)NR¹¹R¹², —SR¹¹, —S(O)R¹⁴, —SO₂R¹⁴, —NR¹¹R¹², —NR¹¹C(O)NR¹²R¹²,—NR¹¹C(NCN)NR¹²R¹³, —OR¹¹, aryl, heteroaryl, arylalkyl, heteroarylalkyl,heterocyclyl and heterocyclylalkyl;

R⁶ is trifluoromethyl, C₁-C₁₀ alkyl, C₃-C₁₀ cycloalkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl, whereinsaid alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,heterocyclyl and heterocyclylalkyl portions are optionally substitutedindependently with one or more groups independently selected from oxo(with the proviso that it is not substituted on an aryl or heteroaryl),halogen, cyano, nitro, trifluoromethyl, difluoromethoxy,trifluoromethoxy, azido, —NR¹¹SO₂R¹⁴, —SO₂NR¹¹R¹², —C(O)R¹¹, —C(O)OR¹¹,—OC(O)R¹¹, —NR¹¹C(O)OR¹⁴, —NR¹¹C(O)R¹², —C(O)NR¹¹R¹², —SR¹¹, —S(O)R¹⁴,—SO₂R¹⁴, —NR¹¹R¹², —NR¹¹C(O)NR¹²R¹³, —NR¹¹C(NCN)NR¹²R¹³, —OR¹¹, aryl,heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, andheterocyclylalkyl;

R¹¹, R¹² and R¹³ independently are hydrogen, lower alkyl, lower alkenyl,aryl and arylalkyl, and R¹⁴ is lower alkyl, lower alkenyl, aryl andarylalkyl,

or any two of R¹¹, R¹², R¹³ and R¹⁴ together with the atom to which theyare attached form a 4 to 10 membered heteroaryl or heterocyclic ring,wherein said alkyl, alkenyl, aryl, arylalkyl, heteroaryl ring andheterocyclic ring are optionally substituted independently with one ormore groups independently selected from halogen, cyano, nitro,trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, aryl,heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl andheterocyclylalkyl:

W is heteroaryl, heterocyclyl, —C(O)OR³, —C(O)NR³R⁴, —C(O)NR⁴OR³,—C(O)R⁴OR³, —C(O)NR⁴SO₂R⁴, —C(O)(C₃-C₁₀ cycloalkyl), —C(O)(C₁-C₁₀alkyl), —C(O)(aryl), —C(O)(heteroaryl), —C(O)(heterocyclyl) or —CR³R³,wherein any of said heteroaryl, heterocyclyl, —C(O)OR³, —C(O)NR³R⁴,—C(O)NR⁴OR³, —C(O)R⁴OR³, —C(O)NR⁴SO₂R³, —C(O)(C₃-C₁₀ cycloalkyl),—C(O)(C₁-C₁₀ alkyl), —C(aryl), —C(O)(heteroaryl), —C(O)(heterocyclyl)and CR³OR³ are optionally substituted independently with one or moregroups independently selected from halogen, cyano, nitro, azido, —NR³R⁴,—OR³, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, cycloalkyl andheterocycloalkyl, wherein any of said C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl,C₂-C₁₀ alkynyl, cycloalkyl and heterocycloalkyl are optionallysubstituted independently with 1 or more groups independently selectedfrom —NR³R⁴ and —OR³;

provided that when X is CH, W cannot be —C(O)aryl or —C(O)heteroaryl;

further provided that when X is CH, W is —C(O)OR³ and R⁹ is F, R⁷ cannotbe H;

m is 0, 1, 2, 3, 4 or 5; and

j is 0, 1 or 2.

In certain embodiments, X is CR¹⁰. In one embodiment, R¹⁰ is H, providedthat when R¹⁰ is H, W cannot be —C(O)aryl or —C(O)heteroaryl, andfurther provided that when R¹⁰ is H, W is C(O)OR³ and R⁹ is F, R⁷ cannotbe H.

In certain embodiments, W is selected from heteroaryl, —C(O)OR³,—C(O)NR³R⁴, —C(O)NR⁴OR³ and —C(O)NR⁴S(O)₂R³.

In another embodiment, W is selected from

FIGS. 15-34 and 37-39 show non-limiting examples of the synthesis ofcompounds of this invention having the general Formula V.

Certain compounds of this invention can exist as two or more tautomericforms. A “tautomer” is one of two or more structural isomers that existin equilibrium and are readily convened from one isomeric form toanother, such as structures formed by the movement of a hydrogen fromone site to another within the same molecule. Other tautomeric forms ofthe compounds may interchange, for example, viaenolization/de-enolization and the like. Accordingly, the presentinvention includes the preparation of all tautomeric forms of compoundsof this invention.

The terms “C₁-C₁₀ alkyl”, “alkyl” and “lower alkyl” as used herein referto a saturated linear or branched-chain monovalent hydrocarbon radicalhaving one to ten carbon atoms, wherein the alkyl radical may beoptionally substituted independently with one or more substituentsdescribed below. Examples of alkyl groups include, but are not limitedto, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, 2-hexyl,3-hexyl, 3-methylpentyl, heptyl, octyl, and the like.

The terms “C₂-C₁₀ alkenyl”, “lower alkenyl” and “alkenyl” refer tolinear or branched-chain monovalent hydrocarbon radical having two to 10carbon atoms and at least one double bond, and include, but is notlimited to ethenyl, propenyl, 1-but-3-enyl, 1-pent-3-enyl, 1-hex-5-enyland the like, wherein the alkenyl radical may be optionally substitutedindependently with one or more substituents described herein, andincludes radicals having “cis” and “trans” orientations, oralternatively, “E” and “Z” orientations.

The terms “C₂-C₁₀ alkynyl,” “lower alkynyl” and “alkynyl” refer to alinear or branched monovalent hydrocarbon radical of two to twelvecarbon atoms containing at least one triple bond. Examples include, butare not limited to, ethynyl, propynyl, butynyl, pentyn-2-yl and thelike, wherein the alkynyl radical may be optionally substitutedindependently with one or more substituents described herein.

The term “allyl” refers to a radical having the formula RC=CHCHR,wherein R is alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl,aryl, heteroaryl, or any substituent as defined herein, wherein theallyl may be optionally substituted independently with one or moresubstituents described herein,

The terms “carbocycle,” “earbocyclyl,” “cycloalkyl” or “C₃-C₁₀cycloalkyl” refer to saturated or partially unsaturated cyclichydrocarbon radical having from three to ten carbon atoms. The term“cycloalkyl” includes monocyclic and polycyclic (e.g. bicyclic andtricyclic) cycloalkyl structures, wherein the polycyclic structuresoptionally include a saturated or partially unsaturated cycloalkyl fusedto a saturated or partially unsaturated cycloalkyl or heterocycloalkylring or an aryl or heteroaryl ring. Examples of cycloalkyl groupsinclude, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, and the like. The cycloalkyl may be optionallysubstituted independently in one or more substitutable positions withvarious groups. For example, such cycloalkyl groups may be optionallysubstituted with, for example, C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen,hydroxy, cyano, nitro, amino, mono(C₁-C₆)alkylamino,di(C₁-C₆)alkylamino, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆ haloalkyl, C₁-C₆haloalkoxy, amino(C₁-C₆)alkyl, mono(C₁-C₆)alkylamino(C₁-C₆)alkyl ordi(C₁-C₆)alkylamino(C₁-C₆)alkyl.

The term “heteroalkyl” refers 10 saturated linear or branched-chainmonovalent hydrocarbon radical of one to twelve carbon atoms, wherein atleast one of the carbon atoms is replaced with a heteroatom selectedfrom N, O, or S, and wherein the radical may be a carbon radical orheteroatom radical (i.e., the heteroatom may appear in the middle or atthe end of the radical). The heteroalkyl radical may be optionallysubstituted independently with one or more substituents describedherein. The term “heteroalkyl” encompasses alkoxy and heteroalkoxyradicals.

The terms “heterocycloalkyl,” “heterocycle” or “heterocyclyl” refer to asaturated or partially unsaturated carbocyclic radical of 3 to 8 ringatoms in which al least one ring atom is a heteroatom selected fromnitrogen, oxygen and sulfur, the remaining ring atoms being C, where oneor more ring atoms may be optionally substituted independently with oneor more substituent described below. The radical may be a carbon radicalor heteroatom radical. The term further includes fused ring systemswhich include a heterocycle fused to one or more aromatic groups.“Heterocycloalkyl” also includes radicals where heterocycle radicals arefused with one or more carbocyclic and/or heterocyclic rings. Examplesof heterocycloalkyl rings include, but are not limited to, pyrrolidinyl,tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl,dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino,thiomorpholino, thioxanyl, piperazinyl, homopiperazinyl, azetidinyl,oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl,diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl,3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl,1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl,dihydrothienyl, dihydrofuranyl, pyrazolidinylimidazolinyl,imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl,azabicyclo[2.2.2]hexanyl, 3H-indolyl and quinolizinyl. Spiro moietiesare also included within the scope of this definition. The foregoinggroups, as derived from the groups listed above, may be C-attached orN-attached where such is possible. For instance, a group derived frompyrrole may be pyrrol-1-yl (N-attached) or pyrrol-3-yl (C-attached).Further, a group derived from imidazole may be imidazol-1-yl(N-attached) or imidazol-3-yl (C-attached). An example of a heterocyclicgroup wherein 2 ring carbon atoms are substituted with oxo (═O) moietiesis 1,1-dioxo-thiomorpholinyl. The heterocycle groups herein areunsubstituted or, as specified, substituted in one or more substitutablepositions with various groups. For example, such heterocycle groups maybe optionally substituted with, for example, C₁-C₆ alkyl, C₁-C₆ alkoxy,halogen, hydroxy, cyano, nitro, amino, mono(C₁-C₆)alkylamino,di(C₁-C₆)alkylamino, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆ haloalkyl, C₁-C₆haloalkoxy, amino(C₁-C₆)alkyl, mono(C₁-C₆)alkylamino(C₁-C₆)alkyl ordi(C₁-C₆)alkylamino(C₁-C₆)alkyl.

The term “aryl” refers to a monovalent aromatic carbocyclic radicalhaving a single ring (e.g., phenyl), multiple rings (e.g., biphenyl), ormultiple condensed rings in which at least one is aromatic, (e.g.,1,2,3,4-tetrahydronaphthyl, naphthyl), which is optionally mono-, di-,or trisubstituted with, e.g., halogen, lower alkyl, lower alkoxy,trifluoromethyl, aryl, heteroaryl, and hydroxy.

The term “heteroaryl” refers to a monovalent aromatic radical of 5-, 6-,or 7-membered rings which includes fused ring systems (at least one ofwhich is aromatic) of 5-10 atoms containing at least one and up to fourheteroatoms selected from nitrogen, oxygen, or sulfur. Examples ofheteroaryl groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl,triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl,oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl,benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl,phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl,oxadiazolyl, triazolyl, thiadiazolyl, thiadiazolyl, furazanyl,benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl,quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. Spiromoieties are also included within the scope of this definition.Heteroaryl groups are optionally mono-, di-, or trisubstituted with,e.g., halogen, lower alkyl, lower alkoxy, haloalkyl, aryl, heteroaryl,and hydroxy.

The term “halogen” represents fluorine, bromine, chlorine, and iodine.

The term “arylalkyl” means an alkyl moiety (as defined above)substituted with one or more aryl moiety (also as defined above). Morepreferred arylalkyl radicals are aryl-C₁₀-alkyls. Examples includebenzyl, phenylethyl, and the like.

The term “heteroarylalkyl” means an alkyl moiety (as defined above)substituted with a heteroaryl moiety (also as defined above). Morepreferred heteroarylalkyl radicals are 5- or 6-memberedheteroaryl-C₁₋₃-alkyls. Examples include, oxazolylmethyl, pyridylethyland the like.

The term “heterocyclylalkyl” means an alkyl moiety (as defined above)substituted with a heterocyclyl moiety (also defined above). Morepreferred heterocyclylalkyl radicals are 5- or 6-memberedheterocyclyl-C₁₋₃-alkyls. Examples include tetrahydropyranylmethyl.

The term “cycloalkylalkyl” means an alkyl moiety (as defined above)substituted with a cycloalkyl moiety (also defined above). Morepreferred heterocyclyl radicals are 5- or 6-memberedcycloalkyl-C₁₋₃-alkyls. Examples include cyclopropylmethyl.

The term “Me” means methyl. “Et” means ethyl, “Bu” means butyl and “Ac”means acetyl.

The term “amino acid residue” includes, but is not limited to, the 20naturally occurring amino acids commonly designated by three lettersymbols, and also includes 4-hydroxyproline, hydroxylysine, demosine,isodemosine, 3-methylhistidine, norvaline, beta-alanine,gamma-aminobutyric acid, cirtulline, homocysteine, homoserine, ornithineand methionine sulfone.

In general, the various moieties or functional groups of the compoundsof Formulas I-V may be optionally substituted by one or moresubstituents. Examples of substituents suitable for purposes of thisinvention include, but are not limited to, oxo (with the proviso that itis not on an aryl or heteroaryl), halogen, cyano, nitro,trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, —NR⁴SO₂R⁶,—SO₂NR³R⁴, —C(O)R³, —C(O)OR³, —OC(O)R³, —NR⁴C(O)OR⁶, —NR⁴C(O)R³,—C(O)NR³R⁴, —NR³R⁴, —NR⁵C(O)NR³R⁴, —NR⁵C(NCN)NR³R⁴, —OR³, aryl,heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, andheterocyclylalkyl, where R³, R⁴, R⁵ and R⁶ are as defined herein.

It is to be understood that in instances where two or more radicals areused in succession to define a substituent attached to a structure, thefirst named radical is considered to be terminal and the last namedradical is considered to be attached to the structure in question. Thus,for example, the radical arylalkyl is attached to the structure inquestion by the alkyl group.

In the compounds of the present invention, where a term such as(CR⁴R⁵)_(m) is used, R⁴ and R⁵ may vary with each iteration of mabove 1. For instance, where m is 2, the term (CR⁴R⁵)_(m) may equal—CH₂CH₂— or —CH(CH₃)C(CH₂CH₃)(CH₂CH₂CH₃)— or any number of similarmoieties falling within the scope of the definitions of R⁴ and R⁵.

The compounds of this invention may possess one or more asymmetriccenters; such compounds can therefore be produced as individual (R)- or(S)-stereoisomers or as mixtures thereof. Unless indicated otherwise,the description or naming of a particular compound in the specificationand claims is intended to include both individual enantiomers,diastereomers mixtures, racemic or otherwise, thereof. Accordingly, thisinvention also includes all such isomers, including diastereomericmixtures and resolved enantiomers of the Formulas I-V. Diastereomericmixtures can be separated into their individual diastereomers on thebasis of their physical chemical differences by methods known to thoseskilled in the art, for example, by chromatography or fractionalcrystallization. Enantiomers can be separated by converting theenantiomer mixture into a diastereomeric mixture by reaction with anappropriate optically active compound (e.g. alcohol), separating thediastereomers and converting (e.g., hydrolyzing) the individualdiastereomers to the corresponding pure enantiomers. The methods for thedetermination of stereochemistry and the separation of stereoisomers arewell known in the art (see discussion in Chapter 4 of “Advanced OrganicChemistry”, 4th edition, J. March, John Wiley and Sons, New York, 1992).

This invention also encompasses pharmaceutical compositions containing acompound of Formula I-V and methods of treating proliferative disorders,or abnormal cell growth, by administering compounds of the presentinvention. Compounds of the present invention having free amino, amido,hydroxy or carboxylic groups can be converted into pharmaceuticallyacceptable prodrugs.

A “prodrug” is a compound that may be converted under physiologicalconditions or by solvolysis to the specified compound or to apharmaceutically acceptable salt of such compound. Prodrugs includecompounds wherein an amino acid residue, or a polypeptide chain of twoor more (e.g., two, three or four) amino acid residues is covalentlyjoined through an amide or ester bond to a free amino, hydroxy orcarboxylic acid group of compounds of the present invention. The aminoacid residues include but are not limited to the 20 naturally occurringamino acids commonly designated by three letter symbols and alsoincludes 4-hydroxyproline, hydroxylysine, demosine, isodemosine,3-methylhistidine, norvaline, beta-alanine, gamma-aminobutyric acid,cirtulline, homocysteine, homoserine, ornithine and methionine sulfone.One preferred prodrug of this invention is a compound of Formula I-Vcovalently joined to a valine residue.

Additional types of prodrugs are also encompassed. For instance, freecarboxyl groups can be derivatized as amides or alkyl esters. As anotherexample, compounds of this invention comprising free hydroxy groups maybe derivatized as prodrugs by converting the hydroxy group to aphosphate ester, hemisuccinates dimethylaminoacetate, orphosphoryloxymethyloxycarbonyl, as outlined in Advanced Drug DeliveryReviews, 1996, 19, 115. Carbamate prodrugs of hydroxy and amino groupsare also included, as are carbonate prodrugs, sulfonate esters andsulfate esters of hydroxy groups. Derivatization of hydroxy groups as(acyloxy)methyl and (acyloxy)ethyl ethers wherein the acyl group may bean alkyl ester, optionally substituted with groups including but notlimited to ether, amine and carboxylic acid functionalities, or wherethe acyl group is an amino acid ester as described above, are alsoencompassed. Prodrugs of this type are described in. J. Med. Chem.,1996, 39, 10. More specific examples include replacement of the hydrogenatom of the alcohol group with a group such as (C₁-C₆)alkanoyloxymethyl,1-((C₁-C₆)alkanoyloxy)ethyl, 1-methyl-1-((C₁-C₆)alkanoyloxy)ethyl,(C₁-C₆)alkoxycarbonyloxymethyl, N—(C₁-C₆)alkoxycarbonyl-aminomethyl,succinoyl, (C₁-C₆)alkanoyl, α-amino(C₁-C₄)alkanoyl, arylacyl andα-aminoacyl, or α-aminoacyl-α-aminoacyl, where each α-aminoacyl group isindependently selected from the naturally occurring L-amino acids,P(O)(OH)₂, —P(O)(O(C₁-C₆)alkyl) or glycosyl (the radical resulting fromthe removal of a hydroxyl group of the hemiacetal form of acarbohydrate).

Free amines can also be derivatized as amides, sulfonamides orphosphonamides. For example, a prodrug can be formed by the replacementof a hydrogen atom in the amine group with a group such as R-carbonyl,RO-carbonyl, NRR′-carbonyl where R and R′ are each independently(C₁-C₁₀)alkyl, (C₃-C₇)cycloalkyl, benzyl, or R-carbonyl is a naturalα-aminoacyl or natural .alpha.-aminoacyl-natural α-aminoacyl,—C(OH)C(O)OY wherein Y is H, (C₁-C₆)alkyl or benzyl, —C(OY₀)Y₁ whereinY₀ is (C₁-C₄) alkyl and Y₁ is (C₁-C₆)alkyl, carboxy(C₁-C₆)alkyl,amino(C₁-C₄)alkyl or mono-N— or di-N,N—(C₁-C₆)alkylaminoalkyl, —C(Y₂)Y₃wherein Y₂ is H or methyl and Y₃ is mono-N— or di-N,N—(C₁-C₆)alkylamino,morpholino, piperidin-1-yl or pyrrolidin-1-yl.

All of these prodrug moieties may incorporate groups including but notlimited to ether, amine and carboxylic acid functionalities.

Prodrugs of a compound of Formula I-V may be identified using routinetechniques known in the art. Various forms of prodrugs are known in theart. For examples of such prodrug derivatives, see, for example, a)Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methodsin Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al.,(Academic Press, 1985): b) A Textbook of Drug Design and Development,edited by Krogsgaard-Larsen and H. Bundgaard. Chapter 5 “Design andApplication of Prodrugs.” by H. Bundgaard p. 113-191 (1991); c) H.Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); d) H.Bundgaard, et al., Journal of Pharmaceutical Sciences, 77:285 (1988):and e) N. Kakeya, et al., Chem. Pharm. Bull., 32:692 (1984), each ofwhich is specifically incorporated herein by reference.

In addition, the invention also includes solvates, metabolites, andpharmaceutically acceptable salts of compounds of Formulas I-V.

The term “solvate” refers to an aggregate of a molecule with one or moresolvent molecules.

A “metabolite” is a pharmacologically active product produced through invivo metabolism in the body of a specified compound or salt thereof.Such products may result for example from the oxidation, reduction,hydrolysis, amidation, deamidation, esterification, deesterification,enzymatic cleavage, and the like, of the administered compound.Accordingly, the invention includes metabolites of compounds of FormulasI-V, including compounds produced by a process comprising contacting acompound of this invention with a mammal for a period of time sufficientto yield a metabolic product thereof.

Metabolites are typically identified by preparing a radiolabelled (e.g.,¹⁴C or ³H) isotope of a compound of the invention, administering itparenterally in a delectable dose (e.g., greater than about 0.5 mg/kg)to an animal such as rat, mouse, guinea pig, monkey, or man, allowingsufficient lime for metabolism to occur (typically about 30 seconds to30 hours) and isolating its conversion products from the urine, blood orother biological samples. These products are easily isolated since theyare labeled (others are isolated by the use of antibodies capable, ofbinding epitopes surviving in the metabolite). The metabolite structuresare determined in conventional fashion, e.g., by MS, LC/MS or NMRanalysis. In general, analysis of metabolites is done in the same way asconventional drug metabolism studies well known to those skilled in theart. The metabolites, so long as they are not otherwise found in vivo,are useful in diagnostic assays for therapeutic dosing of the compoundsof the invention.

A “pharmaceutically acceptable salt” as used herein, unless otherwiseindicated, includes salts that retain the biological effectiveness ofthe free acids and bases of the specified compound and that are notbiologically or otherwise undesirable. A compound of the invention maypossess a sufficiently acidic, a sufficiently basic, or both functionalgroups, and accordingly react with any of a number of inorganic ororganic bases, and inorganic and organic acids, to form apharmaceutically acceptable sale. Examples of pharmaceuticallyacceptable salts include those salts prepared by reaction of thecompounds of the present invention with a mineral or organic acid or aninorganic base, such salts including sulfates, pyrosulfates, bisulfates,sulfites, bisulfites, phosphates, monohydrogenphosphates,dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides,bromides, iodides, acetates, propionates, decanoates, caprylates,acrylates, formates, isobutyrates, caproates, heptanoates, propiolates,oxalates, malonates, succinates, suberates, sebacates, fumarates,maleates, butyn-1,4-dioates, hexyne-1,6-dioates, benzoates,chlorobenzoates, methylbenzoates, dinitromenzoates, hydroxybenzoaies,methoxybenzoates, phthalates, sulfonates, xylenesulfonates,pheylacetates, phenylpropionates, phenylbutyrates, citrates, lactates,γ-hydroxybutyrates, glycollates, tartrates, methanesulfonates,propanesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates,and mandelates. Since a single compound of the present invention mayinclude more than one acidic or basic moieties, the compounds of thepresent invention may include mono, di or tri-salts in a singlecompound.

If the inventive compound is a base, the desired pharmaceuticallyacceptable salt may be prepared by any suitable method available in theart, for example, treatment of the free base with an acidic compound,particularly an inorganic acid, such as hydrochloric acid, hydrobromicacid, sulfuric acid, nitric acid, phosphoric acid and the like, or withan organic acid, such as acetic acid, maleic acid, succinic acid,mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid,glycolic acid, salicylic acid, a pyranosidyl acid, such as glucuronicacid or galacturonic acid, an alphahydroxy acid, such as citric acid ortartaric acid, an amino acid, such as aspartic acid or glutamic acid, anaromatic acid, such as benzoic acid or cinnamic acid, a sulfonic acid,such as p-toluenesulfonic acid or ethanesulfonic acid, or the like.

If the inventive compound is an acid, the desired pharmaceuticallyacceptable salt may be prepared by any suitable method, for example,treatment of the free acid with an inorganic or organic base. Preferredinorganic salts are those formed with alkali and alkaline earth metalssuch as lithium, sodium, potassium, barium and calcium. Preferredorganic base sails include, for example, ammonium, dibenzylammonium,benzylammonium, 2-hydroxyethylammonium, bis(2-hydroxyethyl)ammonium,phenylethylbenxylamine, dibenzyl-ethylenediamine, and the like sails.Other sails of acidic moieties may include, for example, those sailsformed with procaine, quinine and N-methylglusoamine, plus salts formedwith basic amino acids such as glycine, ornithine, histidine,phenylglycine, lysine and arginine.

Processes for the manufacture of the compounds of Formula I, Formula II,Formula III, Formula IV and Formula V are provided as further featuresof the invention. The inventive compounds may be prepared using thereaction routes and synthesis schemes as described below, employing thetechniques available in the art using starting materials that arereadily available or can be synthesized using methods known in the art.

Illustrations of the preparation of compounds of the present inventionare shown in FIGS. 1-34.

FIG. 1 illustrates synthesis of compounds of Formula I. Pyridone ester 2can be prepared in a two-step, one-pot procedure. Treatment of3-oxo-pentanedioic acid diethyl ester 1 with triethyl orthoformate andacetic acid al elevated temperatures (120 to 150° C.) gives theintermediate enol ether. Cyclization of the enol ether intermediate isaccomplished by cooling the concentrated reaction residue and treatingwith the appropriate amine at low temperature (about 0° C.).Halogenation of the pyridone ester 2 can be accomplished with POCl₃,thionyl chloride, oxalyl chloride, PCl₃, PBr₃, or Ph₃P and Br₂. In oneembodiment this transformation is achieved with POCl₃ neat or in thepresence of an amine like triethylamine at room temperature. If R⁹ is Clor F, it can be incorporated at this stage. Chlorination of pyridoneester 3 can be accomplished with NCS in a suitable organic solvent suchas DMF, MeCN or mixed solvent systems at room temperature. In oneembodiment the reaction is carried out in DMF. Fluorination is achievedby treating pyridone ester 3 with[1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane-bis(tetrafluoroborate)in the presence of base in a suitable organic solvent at the appropriatetemperature. Most preferable is the use of LiOH as base and MeCN assolvent at approximately 85° C.

With continued reference to FIG. 1, regardless of the identity of R⁹,pyridone acid 4 can be prepared by basic hydrolysis under standardconditions using either LiOH or NaOH in standard mixed aqueous/organicsolvent systems. Incorporation of the aniline moiety is accomplished byS_(N)Ar reaction. This can be done in a suitable organic solvent such asTHF using an amide base such as LDA, LiHMDS, NaHMDS or KHMDS atappropriate temperatures (−78° C. to room temperature). In oneembodiment, the aniline is added to LDA or LiHMDS in THF at lowtemperature (−20 to −80° C.). The pyridone 4 is then added and thereaction mixture is warmed to room temperature to generate carboxylicacid 5. Amides 6 and hydroxamates 7 can be prepared using standardcoupling procedures, including but not limited to EDCl, HOBt, or PyBOPand the appropriate amine or hydroxylamine in suitable organic solventssuch as DMF. THF or methylene chloride. In some instances, the amine orhydroxylamine used in the coupling reaction contains a standardprotecting group. In those cases, the protecting group can be removed bystandard conditions known in the art.

FIG. 2 outlines the synthesis of compounds of Formula I wherein the R⁹group is incorporated into the starting 3-oxopentanedioic acid diethylester 8. This route is particularly useful for analogs where R⁹ isalkyl. The preparation of analog 10 is outlined in FIG. 2 and can becarried out as described above for FIG. 1 with the addition thatactivation of pyridone 9 can be accomplished by conversion to a triflateester. For example, treating pyridone 9 with triflic anhydride orN-phenyltrifluoromethanesulfonimide and amine base in THF or methylenechloride. When Z is Cl or Br, pyridone 10 can be converted to amide 6 orhydroxmate 7 as described in FIG. 1. Alternatively, pyridone 10 can beconverted to hydroxamate 7 in the route outlined in FIG. 2 in which theaniline moiety is incorporated utilizing palladium mediated crosscoupling chemistry. The palladium mediated cross coupling chemistry canbe accomplished by treatment of a mixture of the appropriate aniline andpyridone 10 with a Pd catalyst such as Pd(OAc)₂, PdCl₂(dppf), Pd(Ph₃P)₄,Pd₂dba₃, a phosphine ligand and base in a suitable organic solvent suchas THF, DMF, PhMe, DME or MeCN al elevated temperature. In oneembodiment, Pd(OAc)₂, rac-2,2-bis(diphenylphosphino)-1,1-binaphthyl andCs₂CO₃, are used in PhMe at 70 to 100° C. Hydroxamate 7 can be preparedby treating pyridone ester 11 with the appropriate hydroxylamine andamide base such as LDA, LiHMDS or NaHMDS in a suitable organic solventsuch as THF at low temperature. In one embodiment, a LiHMDS solution isadded to a solution of pyridone ester 11 and hydroxylamine in THF at 0°C. The reaction mixture is then warmed to room temperature to yield thedesired hydroxamate 7. In some instances, the hydroxylamine used in thecoupling reaction contains a standard protecting group. In those cases,the protecting group can be removed by standard conditions known in theart.

In FIG. 3 preparation of compounds of the Formula I is shown in which4,6-dichloro-5-fluoronicotinic acid 12 (Sanchez et al., J. Heterocyle.Chem. 1993, 30 (4), 855-9) is used as the starting material. Ester 13can be prepared in a two-step procedure. The first step is S_(N)Araddition of the properly substituted aniline in a suitable organicsolvent such as THF using an amide base such as LDA, LiHMDS. NaHMDS orKHMDS at appropriate temperatures (−78° C. to room temperature). In oneembodiment, the aniline is added to LDA or LiHMDS in THF at lowtemperature (−20 to −80° C.). The nicotinic acid 12 is then added andthe reaction mixture warmed to room temperature to generate thecorresponding carboxylic acid. The methyl ester 13 can then be preparedby standard conditions including but not limited to TMSCl in MeOH orTMSCHN₂ in suitable organic solvents such as PhMe/MeOH. Pyridone 14 canbe made in a two-step sequence. In the first step, methyl ester 13 istreated with sodium methoxide in a suitable organic solvent such as MeOHor THF or MeOH/THF mixtures at temperatures ranging from 0° C. to 40° C.In one embodiment, sodium methoxide is added to a solution of methylester 13 in MeOH/THF at 0° C. This mixture is then warmed to roomtemperature and then to 40° C. to generate the desired methoxy pyridine.Demethylation can then be accomplished by standard conditions includingbut not limited to aqueous HCl at elevated temperature, pTsOH in aceticacid at elevated temperature and aqueous HBr in MeOH at elevatedtemperature. In one embodiment demethylation to give pyridone 14 isachieved by treatment of the methoxy pyridine with HBr in acetic acid atelevated temperature (80 to 120° C.). If desired, alkylation of pyridone14 to give substituted pyridone 15 can be achieved by standard basicalkylation conditions incorporating alkyl halides. These conditionsinclude but are not limited to K₂CO₃ in acetone or DMF, nah in THF or,NaOMe in MeOH/PhMe or, phase transfer conditions using for example NaOHand Bu₄NI. In one embodiment, the alkylation is accomplished bytreatment of pyridone 14 with LiH al 0° C. in DMF followed by additionof alkyl bromide and warming to room temperature. Carboxylic acid 15 canthen be prepared using standard saponification conditions such as LiOHor NaOH in standard mixed aqueous/organic solvent systems. Pyridone 15can be converted to amide 6 or hydroxmate 7 as described in FIG. 1.

FIG. 4 describes the initial steps in the preparation of analogs ofcompounds of the Formula I. Treatment of 3-oxopentanedioic acid diethylester 8 with a ketene acetal and acetic acid at elevated temperatures(120 to 150° C.) gives the intermediate enol ether. Cyclization of theenol ether intermediate can be accomplished by cooling the concentratedreaction residue and treating with the appropriate amine at lowtemperature (about 0° C.) to give pyridone 16. If R⁹ is cl or F isdesired, then a chlorination or fluorination step as described in FIG. 1can be incorporated at this time. Furthermore, pyridone 16 can beconverted to amide 6 or hydroxamate 7 through the S_(N)Ar chemistry asdescribed in FIG. 1 or through palladium mediated cross-couplingchemistry as described in FIG. 2.

In FIG. 5 syntheses of compounds of Formula II and IV are depicted.Bromination of pyridone 17 (prepared as described in FIGS. 2 and 4) togive pyridone 18 can be accomplished using standard conditions such asNBS in a suitable organic solvent. Cyclization to form lactam 19 can beachieved by treatment with ammonia or a primary amine in a suitableorganic solvent at temperatures ranging from ambient to slightlyelevated temperatures. In one embodiment, this cyclization isaccomplished in an alcoholic solvent such as MeOH or EtOH. Pyridone 18can also be converted to pyridazinones 20 and 21 by treatment withsubstituted or unsubstituted hydrazines or t-butyl carbazate in asuitable organic solvent such as DMF, THF, MeOH or EtOH. Pyridazinones20 and 21 can then be substituted further by standard basic alkylationconditions with alkyl halides. These conditions include but are notlimited to K₂CO₃ in acetone or DMF at room or elevated temperature, NaHin THF or DMF at ambient or elevated temperature, and NaOMe in MeOH/PhMeat elevated temperature. Pyridazinone 21 can then be deprotected understandard conditions including, but not limited to, TFA in methylenechloride or HCl in a suitable organic solvent such as dioxane.

FIG. 6 depicts the preparation of compounds of the Formula I where X isN. In FIG. 6,4-hydroxy-6-oxo-1-phenyl-1,6-dihydropyridazine-3-carboxylic acid methylester 24 (Schober, et al., J. Heterocycle. Chem. 1989, 26, 169-176) canbe converted to dihydropyridazine 25 in one of two procedures. The firstmethod involves halogenation followed by S_(N)Ar reaction and in situsaponification. Halogenation of the pyridazine ester 24 can beaccomplished with POCl₃, thionyl chloride, oxalyl chloride, PCl₅, PBr₃,or Ph₃P and Br₂. In one embodiment this transformation is achieved withPOCl₃ neat at elevated temperature (about 85° C.). If R⁹ is Cl or F isdesired, then chlorination or fluorination as described in FIG. 1 can beincorporated at this lime. In the second step, aniline addition andsaponification can be carried out in the same pot. The S_(N)Ar reactioncan be done in a suitable organic solvent such as 1,2-dichlorobenzene,xylenes, or toluene in the presence of a base such as Cs₂CO₃ or K₂CO₃ atelevated temperature (80 to 200° C.). In one embodiment the S_(N)Arreaction is accomplished by treating the halogenated pyridazine withaniline and Cs₂CO₃ in 1,2-dichlorobenzene and heating to 180° C. for 24hours. Saponification to generate dihydropyridazine 25 is accomplishedby the addition of water to the crude reaction mixture stirring at roomtemperature. The second method involves halogenation or activation ofpyridazine ester 24 followed by palladium-mediated cross-coupling.Halogenation is accomplished as described above. Activation isaccomplished by treating pyridazine ester 24 with triflic anhydride orN-phenyltrifluoromethanesulfonimide and amine base in THF or methylenechloride. In the case where halogenation is used, if R⁹ is Cl or F isdesired, then a chlorination or fluorination step as described in FIG. 1can be incorporated at this lime. The palladium-mediated cross-couplingreaction can be achieved by standard methods including bin not limitedto treating the halogenated or activated pyridazine with aniline, Pdcatalyst such as Pd(OAc)₂, PdCl₂(dppf), Pd(Ph₃P)₄, Pd₂dba₃, a phosphineligand and base in a suitable organic solvent such as THF, DMF, PhMe,DME or MeCN at elevated temperature. Saponification to generateddihydropyridazine 25 can be achieved as described above by the additionof water to the crude reaction mixture stirring at room temperature orby basic hydrolysis under standard conditions using either LiOH or NaOHin standard mixed aqueous/organic solvent systems. Dihydropyridazine 25can be converted to amide 26 or hydroxmate 27 by the standard methodsdescribed in FIG. 1 or FIG. 2.

The preparation of compounds of the Formula I where X=N is depicted inFIG. 7. Substituted hydrazine 28 can be converted to hydrazono-propionicacid ethyl ester 29 by a two-step procedure. In the first step,hydrazine 28 is condensed with ethyl pyruvate under standard dehydratingconditions such as in the presence of MgSO₄ in a suitable organicsolvent such as chloroform or methylene chloride at temperatures rangingfrom 0° C. to ambient temperature. In the second step, acylation isachieved by treatment with base at low temperature in a suitable organicsolvent such as THF, DMF, dioxane or MeCN followed by the addition ofmethyl malonyl chloride. In one embodiment, the hydrazone is treatedwith LiH in THF at 0° C. followed by the addition of methyl malonylchloride and warming to room temperature. 5-Hydroxy-2H-pyridazin-3-one31 is prepared from hydrazono-propionic acid ethyl ester 29 bycyclization under strongly basic conditions followed by saponificationand decarboxylation. The cyclization can be accomplished by treatment ofhydrazono-propionic acid ethyl ester 29 with a strong base such as DBU,LDA or NaH in a suitable organic solvent such as THF or MeCN at roomtemperature. In one embodiment, cyclization is achieved with DBU in MeCNat room temperature. Decarboxylation to form5-hydroxy-2H-pyridazin-3-one 31 can be achieved by heating5-hydroxy-3-oxo-2,3-dihydropyridazine-4-carboxylic acid methyl ester 30in a suitable organic solvent such as dioxane or decalin ordioxane/decalin mixture to high temperatures in the presence ofconcentrated HCl. 5-Chloro-2H-pyridazin-3-one 32 can be prepared from5-hydroxy-2H-pyridazin-3-one 31 by treatment with POCl₃, thionylchloride, oxalyl chloride or PCl₅. In one embodiment this transformationis achieved with POCl₃ neat al elevated temperature (˜85° C.). If R⁹ isCl or F is desired, then a chlorination or fluorination step asdescribed in FIG. 1 can be incorporated either after decarboxylation orafter chlorination. Carboxylic acid 33 can be prepared by oxidationunder standard conditions including but not limited to KMnO₄ in water,SeO₄ in organic solvent like dioxane, xylene, or pyridine, NaOCl/RuCl₃,CrO₃ in aqueous H₂SO₄, K₂Cr₂O₇, and Na₂Cr₂O₇ in water. In one embodimentthis transformation is achieved with K₂Cr₂O₇—H₂SO₄. Carboxylic acid 33can be convened to amide 26 or hydroxmate 27 by the standard methodssuch as those described in FIGS. 1, 2 and 6.

FIG. 8 illustrates the preparation of compounds of Formula III. Pyridone11 can be converted to bromide 34 with standard reagents including butnot limited to NBS or bromine with or without a variety of additivessuch as AcOH, H₂O₂, silica. AlCl₃ and t-BuNH₂, in a suitable solventsuch as CCl₄ or water. Synthesis of ketone 35 can be accomplished in atwo-step procedure. In the first step, palladium mediated alkyne crosscoupling reaction is used to generate the corresponding alkyneintermediate. This palladium-mediated cross-coupling reaction can beachieved by standard methods including but not limited to treatingbromide 34 with the desired alkyne, a Pd catalyst such as Pd(OAc)₂ andPh₃P, PdCl₂(dppf), Pd(Ph₃P)₂Cl₂, Pd(Ph₃P)₄ or Pd₂ dba₃ and Ph₃P, CuI,and amine base such as Et₃N, Et₃NH, or iPr₂NH, in a suitable organicsolvent such as THF, DMF, PhMe, DME or MeCN at elevated temperature. Inone embodiment, the bromide 34 and alkyne are treated with Pd(Ph₃P)₂Cl₂,CuI and amine base in THF or DMF at 50 to 100° C. In the second step,the intermediate alkyne is hydrolysized to the ketone 35 by standardmethods including, but not limited to, H₂SO₄, TFA, trifluorosulfonamide,FeCl₃ or HgSO₄H2SO₄. Cyclization to form pyrido-pyridazine-dione 36 canbe accomplished by treating ketone 35 with substituted or unsubstitutedhydrazine in a suitable organic solvent such as EtOH, iPrOH, DMF, DME ormixtures thereof at temperatures ranging from ambient to about 100° C.

Compounds of Formula III can be prepared as outlined in FIG. 9. Bromide37 can be synthesized from pyridone 9 by chlorination followed byaromatic bromination. The chlorination can be accomplished with POCl₃,thionyl chloride, oxalyl chloride, PCl₅, PBr₃, or Ph₃P and Br₂. In oneembodiment this transformation is achieved with POCl₃ neat at elevatedtemperature (about 85° C.). If R⁹=Cl or F is desired, then achlorination or fluorination step as described in FIG. 1 can beincorporated at this time. Aromatic bromination can be achieved withstandard reagents including but not limited to NBS or bromine with orwithout a variety of additives such as AcOH, H₂O₂, silica, AlCl₃ andt-BuNH₂, in a suitable solvent such as CCl₄ or water. Ketone 38 andpyrido-pyridazine-dione 39 can be prepared as described in FIG. 8.Pyridopyridazine-dione 40 can be made from pyridopyridazine-dione 39 bypalladium-mediated cross-coupling chemistry. The palladium-mediatedcross-coupling reaction can be achieved by standard methods including,but not limited to, treating pyridopyridazine-dione 39 with theappropriate aniline, a Pd catalyst such as Pd(OAc)₂, PdCl₂(dppf),Pd(Ph₃P)₄, Pd₂dba₃, a phosphine ligand and base in a suitable organicsolvent such as THF, DMF, PhMe, DME or MeCN at elevated temperature.

FIGS. 10-12 illustrate the preparation of compounds of Formula I of thepresent invention where W is heterocyclic or heteroaromatic. Hydrazide42 can be prepared from carboxylic acid 41 using standard couplingreagents including but not limited to EDCl, HOBt, or PyBOP and hydrazinein suitable organic solvents such as DMF, THF or dichloromethane. Aminooxadiazole 43 is prepared from hydrazide 42 by treatment with BrCN and abase such as NaHCO₃, in a suitable biphasic solvent system such asdioxane and water at room temperature. Oxadiazolone 44 can be preparedfrom hydrazide 42 using CDI, phosgene or a phosgene equivalent in asuitable organic solvent such as DMF, PhMe, methylene chloride ormixtures thereof. In one embodiment, cyclization to form oxadiazolone 44is accomplished by treating hydrazide 42 with CDI in DMF at roomtemperature. Amino triazole 45 can be prepared by treatment of thehydrazide 42 with cyanamide, followed by cyclization using PPh₃, TEA,and CCl₄ in dichloromethane. Similarly, triazole 46 can be prepared bytreatment of the hydrazide 42 with ethyl acetimidate, followed bycyclization using PPh₃, TEA, and CCl₄ in dichloromethane. Substitutedamino oxadiazole 47 can be prepared in a two-step procedure fromoxadiazolone 44 as outlined in FIG. 11. Oxadiazolone 44 is treated witha primary or secondary amine at elevated temperature in alcoholicsolvents such as MeOH. EtOH or iPrOH. In one embodiment, a primary orsecondary amine is stirred with oxadiazolone 44 in EtOH at approximately90° C. The ring-opened intermediate is then cyclized by treatment withPPh₃. TEA, and CCl₄ in dichloromethane to give substituted aminooxadiazole 47. In some cases the primary or secondary amine used in theaddition step contains a functionality that requires protection with astandard protecting group. In these cases, the protecting group can beremoved under standard conditions to yield the desired, substituted,amino oxadiazole 47. The thiazole 48 can be prepared from the carboxylicacid 41 with thiosemicarbazide using standard EDCl coupling conditionsfollowed by cyclization of the intermediate obtained employing PPh₃,TEA, and CCl₄ in dichloromethane as outlined in FIG. 12.

FIG. 13 illustrates the preparation of compounds of Formula I. Acylsulfonamide 49 can be prepared from carboxylic acid 41 using standardcoupling reagents including but not limited to CDI or EDCl, HOBt, orPyBOP and the appropriate sulfonamide in suitable organic solvents suchas DMF, THF or dichloromethane in the presence of base. In oneembodiment, carboxylic acid 41 is treated with CDI in DMF at roomtemperature followed, a few hours later, by the addition of theappropriate sulfonamide and DBU.

FIG. 14 illustrates the synthesis of compounds of Formula I where W is aketone. Ketone 51 can be prepared either by treating methyl ester 50with Tebbe's reagent followed by aqueous acid or in a four-stepoxidative reduction protocol which includes addition of an alkyllithiumor Grignard reagent to the corresponding aldehyde. The four-stepprotocol can be accomplished as follows. The methyl ester 50 is reducedwith NaBrH₄ in EtOH at room temperature followed by oxidation with MnO₂in THF:acetone at 50° C. to give the corresponding aldehyde. Thesecondary alcohol is then prepared by adding either a Grignard reagentor an alkyllithium to the aldehyde at −78° C. The ketone 51 is thenprepared by MnO₂ oxidation of the corresponding secondary alcohol inTHF:acetone at 50° C.

In FIG. 15, the syntheses of compounds of Formula V where X is CH and R⁹is H or F is depicted, in which 2,6-dichloronicotinic acid or2,6-dichloro-5-fluoronicotinic acid is used as the starting material.The nicotinic acid 52 is converted to the monochloro acid 53 byrefluxing in 2N aqueous NaOH following the procedure described in U.S.Pat. No. 3,682,932. Alkylation of 53 can be achieved by standard basicalkylation conditions incorporating alkyl halides, with two equivalentsof the appropriate alkyl halide and base to give a mixture of theN-alkyl pyridone ester and the regioisomeric O-alkyl pyridine ester,which are easily separated by column chromatography. These conditionsinclude but are not limited to K₂CO₃ in acetone or DMF at room orelevated temperature or NaH in THF at ambient or elevated temperature,followed by the addition of an alkyl halide. In one embodiment thisalkylation is achieved with LiH in DMF at 0° C. followed by addition ofalkyl bromide or alkyl iodide and warming to room temperature.Incorporation of the properly substituted aniline moiety is accomplishedby S_(N)AR reaction. This can be done in a suitable organic solvent suchas THF using an amide base such as LDA, LiHMDS, NaHMDS or KHMDS atappropriate temperatures (−78° C. to room temperature). In oneembodiment the aniline is added to LDA or LiHMDS in THF at lowtemperature (−20 to −80° C.). The pyridone is then added and the mixtureis stirred at low temperature to generate ester 54. Carboxylic acid 55can then be prepared using standard saponification conditions such asLiOH or NaOH in standard mixed aqueous/organic solvent systems.Hydroxamate 56 and amide 57 can be prepared using standard couplingprocedures, including but not limited to EDCl, HOBt, or PyBOP and theappropriate amine or hydroxylamine in suitable organic solvents such asDMF, THF, or methylene chloride. In one embodiment, the coupling isaccomplished with HOBt and EDCl in DMF. In some instances, the amine orhydroxylamine used in the coupling reaction contains a standardprotecting group. In those cases, the protecting group can be removed bystandard conditions known in the art.

In FIG. 16, an alternative synthesis of compounds of Formula V where Xis CH and R⁹ is H or F is depicted, in which 2,6-dichloronicotinic acidor 2,6-dichloro-5-fluoronicotinic acid is used as the starting material.This route is particularly useful for analogs where R⁷ is not Me or Et.Nicotinic acid 52 can be converted to the N-alkyl pyridone methyl ester54 following a five step procedure, where 2,6-dichloronicotinic acid 52is first convened to the methoxy pyridine acid, which is esterified togive the methyl ester and then deprotected to yield the monochloro ester58. In one embodiment, the conversion to the methoxypyridine acid iscarried out by adding potassium t-butoxide to a solution of the acid 52in MeOH, and the reaction mixture is heated to reflux for several days.Esterification to give the methyl ester can be carried out understandard conditions including, but not limited to, Fisher esterification(MeOH, H₂SO₄), TMSCl in MeOH or TMSCHN₂ in suitable organic solventssuch as PhMe/MeOH. Demethylation of the methoxy pyridine can then beaccomplished by standard conditions including but hot limited to HCl atelevated temperature, pTsOH in acetic acid at elevated temperature andaqueous HBr in MeOH at elevated temperature. Demethylation to givepyridone 58 is achieved by treatment of the methoxypyridine with aqueousHBr in acetic acid at elevated temperature (80 to 320° C.). Alkylationof 58 can be achieved by standard basic alkylation conditionsincorporating alkyl halides, with one equivalent of the appropriatealkyl halide and base to give a mixture of the N-alkyl pyridone esterand the regioisomeric O-alkyl pyridine ester, which are easily separatedby column chromatography. These conditions include but are not limitedto K₂O₃in acetone or DMF at room or elevated temperature or NaH in THFat ambient or elevated temperature and then addition of the alkylhalide. For example, in one embodiment alkylation is achieved with LiHin DMF at 0° C., followed by addition of alkyl bromide or alkyl iodideand warming to room temperature. Incorporation of the properlysubstituted aniline moiety is accomplished by S_(N)AR reaction. This canbe done in a suitable organic solvent such as THF using an amide basesuch as LDA, LiHMDS, NaHMDS, or KHMDS at appropriate temperatures (−78°C. to room temperature. In one embodiment, the aniline is added to LDAor LiHMDS in THF al low temperature (−20 to −80° C.). The pyridone isthen added and the mixture is stirred at low temperature to generateester 54. Hydroxamate 56 can be prepared directly from methyl ester 54in a suitable organic solvent such as THF using the appropriatehydroxylamine and amide base such as LDA, LiHMDS, NaHMDS, or KHMDS atappropriate temperatures (−78° C. to room temperature). In oneembodiment, a solution of LiHMDS is added to a solution of the methylester 54 and the hydroxylamine in THF at 0° C. The reaction mixture isthen warmed to room temperature to yield the desired hydroxamate 56. Insome instances, the hydroxylamine used in the coupling reaction containsa standard protecting group. In those cases, the protecting group can beremoved by standard conditions known in the art.

In FIG. 17, another alternative synthesis of compounds of Formula Vwhere X is CH and R⁹ is H or F and R⁷ is H is depicted, in which either2,6-dichloronicotinic acid or 2,6-dichloro-5-fluoronicoiinic acid isused as the starting material. Formation of 59 is accomplished byincorporation of the properly substituted aniline moiety into nicotinicacid 52 by S_(N)AR reaction. This can be done in a suitable organicsolvent such as THF using an amide base such as LDA, LiHMDS, NaHMDS, orKHMDS at appropriate temperatures (−78° C. to room temperature. In oneembodiment the aniline is added to LDA or LiHMDS in THF at lowtemperature (−20 to −80° C.). Nicotinic acid 52 is then added and themixture is stirred at low temperature to generate the coupled product.Esterification to give the methyl ester can be carried out understandard conditions, including but not limited to Fisher esterification(MeOH, H2SO₄). TMSCl in MeOH or TMSCHN₂ in suitable organic solventssuch as PhMe/MeOH. Pyridone 54 can be made in a two-step sequence. Inthe first step, methyl ester 59 is treated with sodium methoxide in asuitable organic solvent such as MeOH or THF or MeOH/THF mixtures attemperatures ranging from 0° C. to reflux. In one embodiment, sodiummethoxide is added to a solution of methyl ester 59 in MeOH at roomtemperature. This mixture is then refluxed for 4 days to generate thedesired methoxypyridine. Demelhylation of the methoxypyridine can thenbe accomplished by standard conditions including but not limited to HClat elevated temperature, pTsOH in acetic acid at elevated temperatureand aqueous HBr in MeOH at elevated temperature. Preferabledemethylalion to give pyridone 54 is achieved by treatment of themethoxypyridine with aqueous HBr in acetic acid at elevated temperature(80 to 120° C.). Carboxylic acid 55, as well as hydroxamate 56 and amide57 can then be prepared as described for FIG. 15.

In FIG. 18, the synthesis of compounds of Formula V where X is CH and R⁸is not H is depicted, in which 2,6-dichloronicotinic acid is used as thestarting material. Bromination of pyridone ester 54 can be accomplishedwith either Br and acetic acid or NBS in a suitable organic solvent suchas DMF. In one embodiment NBS is added to a solution of pyridone ester54 in DMF to yield 60. Conversion of 60 to carboxylic acid 55, as wellas hydroxamate 56 and amide 57 (where R⁹ is Br) can be accomplished asdescribed for FIGS. 15 and/or 16. Conversion of bromide 60 to compoundsof Formula V where R⁹ is aryl, heteroaryl, alkyl, cycloalkyl, alkenyl,alkynyl, amino or anilino can be achieved using palladium-mediatedcross-coupling conditions. When R⁹ of Formula V is alkenyl or alkynyl,these compounds can be further reduced using the appropriate reducingagent to provide alkyl substituents at R⁹. In general, this chemistrycan be accomplished using a wide variety of Pd catalysts and ligands,with or without added base, in a suitable organic solvent such as DMF.PhMe, DME, THF, CH₃CN at elevated temperature. The coupling partner willdepend on the nature of R⁹. These palladium-mediated cross-couplingreactions are well documented in the literature and are known by anyoneskilled in the art. Conversion of 54 to carboxylic acid 55, as well ashydroxamate 56 and amide 57 can be accomplished as described for FIGS.15 and/or 16.

In FIG. 19, the synthesis of compounds of Formula V is depicted, where Xis N. Pyrazinone ester 61, which can be synthesized as shown in FIG. 21or 22, can be converted to carboxylic acid 62 using standardsaponification conditions such as LiOH or NaOH in standard mixedaqueous/organic solvent systems. Hydroxamate 63 and amide 64 can beprepared using standard coupling procedures, including but not limitedto EDCl, HOBt, or PyBOP and the appropriate amine or hydroxylamine insuitable organic solvents such as DMF. THF, or methylene chloride. Insome instances, the amine or hydroxylamine used in the coupling reactioncontains a standard protecting group. In those cases, the protectinggroup can be removed by standard conditions known in the art.

In FIG. 20, the synthesis of compounds of Formula V is depicted, where Xis N. Pyrazinone ester 61, which can be synthesized as shown in FIG. 21or 22, can be directly converted to hydroxamate 63 in a suitable organicsolvent such as THF using the appropriate hydroxylamine and an amidebase such as LDA, LiHMDS, NaHMDS or KHMDS at appropriate temperatures(−78° C. to room temperature). In some instances, the hydroxylamine usedin the coupling reaction contains a standard protecting group. In thosecases, the protecting group can be removed by standard conditions knownin the art.

In FIG. 21, the synthesis of pyrazinone ester 61, which is utilized asstarting material in FIGS. 19 and 20, is depicted. The aniline moiety isincorporated into aminopyrazinone 65 utilizing palladium-mediatedcross-coupling chemistry. The palladium-mediated cross couplingchemistry can be accomplished by treating a mixture of aniline andaminopyrazinone 65 with a Pd catalyst such as Pd(OAc)₂, PdCl₂(dppf),Pd(Ph₃P)₄, or Pd₂dba₃, a phosphine ligand and base in a suitable organicsolvent such as THF, DMF, PhMe. DME or MeCN al elevated temperature. IfR⁸ is Br or I, then a bromination or iodination step can be incorporatedafter the cross-coupling reaction. Thus, halogenation of 66 can beaccomplished with either NIS or NBS in a suitable organic solvent suchas DMF, MeCN or mixed solvent systems at room temperature to provide 61.

In FIG. 22, an alternative synthesis of pyrazinone ester 61, which isutilized as starting material in FIGS. 19 and 20, is depicted.Diazotization of 61 with nitrous acid in the presence of sulfuric acidyields the diazonium salt, which can be further reacted with HBr andCuBr to yield bromide 67. Formation of 61 can then be accomplished byincorporation of the properly substituted aniline moiety into bromide 67by an S_(N)AR reaction. This can be done in a suitable organic solventsuch as THF using an amide base such as LDA, LiHMDS, NaHMDS, or KHMDS alappropriate temperatures (−78° C. to room temperature). In oneembodiment the aniline is added to LDA or LiHMDS in THF at lowtemperature (−20 to −80° C.). Bromide 67 is then added and the mixtureis stirred at low temperature to generate the coupled product 61.

In FIGS. 23-27, several syntheses of aminopyrazinone 65, which is usedas the starting material in FIGS. 21 and 22, are depicted, depending onthe identity of R⁹. FIG. 23 depicts the synthesis of the aminopyrazinonecore where R⁹ is H, 3-Amino-5-oxo-4,5-dihydropyrazine-2-carboxylic acidethyl ester 68 can be synthesized as described in the literature(Journal of Organic Chemistry 1975, 40, 2341-2346). Alkylation of 68 canbe achieved by standard basic alkylation conditions incorporating alkylhalides, using one equivalent of the appropriate alkyl halide and baseto give a mixture of the N-alkyl pyrazinone 65 (R⁹ is H) and theregioisomeric O-alkyl pyrazine, which can be separated by columnchromatography. These reaction conditions include but are not limited toK₂CO₃ in acetone or DMF at room or elevated temperature or NaH in THF atambient or elevated temperature and then addition of the alkyl halide.

FIG. 24 depicts the synthesis of an aminopyrazinone core structure whereR⁹=Me. 3-Amino-6-methylpyrazine-2-carboxylic acid ethyl ester N-oxide 69can be synthesized as described in the literature (J. HeterocyclicChemistry 1987, 24, 1621-1628). Rearrangement of N-oxide 69 can beachieved with either acetic anhydride and acetic acid or trifluoroaceticanhydride and trifluoroacetic acid, which is then followed bydeprotection with MeOH or EtOH to provide 70. Alkylation of 70 can beachieved by standard basic alkylation conditions incorporating alkylhalides, with one equivalent of the appropriate alkyl halide and base togive a mixture of the N-alkyl pyrazinone 65 (R⁹=Me) and theregioisomeric O-alkyl pyrazine, which can be separated by columnchromatography. These conditions include but are not limited to K₂CO₃ inacetone or DMF at room or elevated temperature or NaH in THF at ambientor elevated temperature and then addition of the alkyl halide.

FIG. 25 also depicts the synthesis of an aminopyrazinone core structurewhere R⁹= Me. 3-Amino-5-chloro-6-methylpyrazine-2-carbonitrile 71 can besynthesized as described in the literature (J. Heterocyclic Chemistry1987, 24, 1621-1628). Pyrazinone 72 can be made in a two-step sequence.In the first step, pyrazine 71 is treated with sodium methoxide in asuitable organic solvent such as MeOH or THF or MeOH/THF mixture attemperatures ranging from 0° C. to reflux. Demethylation of the methoxypyrazine to provide 72 can then be accomplished by standard conditionsincluding but not limited to pTsOH in acetic acid at elevatedtemperature or aqueous HBr in MeOH at elevated temperature. Alkylationof 72 can be achieved by standard basic alkylation conditionsincorporating alkyl halides, using one equivalent of the appropriatealkyl halide and base to give a mixture of the N-allyl pyrazinone 73 andthe regioisomeric. O-alkyl pyrazine, which can be separated by columnchromatography. These conditions include but are not limited to K₂CO₃ inacetone or DMF al room or elevated temperature or NaH in THF at ambientor elevated temperature, followed by the addition of an alkyl halide.Hydrolysis of nitrile 73 is followed by esterification to give ester 65(R⁹= Me). Hydrolysis of the nitrite can be achieved with either anacidic or basic aqueous solution including but not limited to aqueousHCl, KOH, or NaOH. Esterification to give the methyl ester 65 (R⁹=Me)can be carried out under standard conditions, including but not limitedto Fisher esterification (MeOH, H₂SO₄), TMSCl in MeOH or TMSCHN₂ insuitable organic solvents such as PhMe/MeOH.

FIG. 26 depicts the synthesis of an aminopyrazinone core structure whereR⁹ is —C(═O)H. A protected oxime analog,3-amino-6-(benzyliminomethyl)-pyrazine-2-carboxylic acid ethyl esterN-oxide 74, can be synthesized as described in the literature (JustusLiebigs Annalen der Chemie 1969, 726, 100-102), with the use ofO-benzyl-hydroxylamine in place of hydroxylamine. Protection of theoxime functionality with a standard protecting group includes, but isnot limited to O-benzyl. This is followed by rearrangement of N-oxide 74with either acetic anhydride and acetic acid or trifluoroaceticanhydride and trifluoroacetic acid. Removal of the N-acyl functionalityof 75 can be achieved with MeOH or EtOH to provide 76. Alkylation of 76can be achieved by standard basic alkylation conditions incorporatingalkyl halides, with one equivalent of the appropriate alkyl halide andbase to give a mixture of the N-alkyl pyrazinone 77 and theregioisomeric O-alkyl pyrazine, which can be separated by columnchromatography. These conditions include but are not limited to K₂CO₃ inacetone or DMF at room or elevated temperature or NaH in THF at ambientor elevated temperature, followed by the addition of the alkyl halide.Deprotection of oxime 77 is followed by cleavage to the aldehyde 65(R⁹=—C(O)H). Deprotection of the oxime depends on the nature of theprotecting group chosen. If the protecting group chosen is benzyl, itcan be removed under catalytic hydrogenation conditions with a suitablePd or Pt catalyst, including but not limited to Pd—C or PtO₂ under anatmosphere of hydrogen in a suitable organic solvent. Conversion ofoxime to aldehyde 65 (R⁹=—C(O)H) can be achieved under hydrolysisconditions, including but not limited to aqueous HCl in an appropriateorganic solvent such as dioxane.

FIG. 27 depicts the synthesis of an aminopyrazinone core structure whereR⁹ is Cl. 3-Amino-6-Chloro-5-oxo-4,5-dihydropyrazine-2-carboxylic acidmethyl ester 78 can be synthesized as described in the literature (J.Medicinal Chemistry 1967, 10, 66-75). Alkylation of 78 can be achievedby standard basic alkylation conditions incorporating alkyl halides,with one equivalent of the appropriate alkyl halide and base to give amixture of the N-alkyl pyrazinone 65 (R⁹= Cl) and the regioisomericO-alkyl pyrazine, which can be separated by column chromatography. Theseconditions include but are not limited to K₂CO3in acetone or DMF at roomor elevated temperature or NaH in THF at ambient or elevatedtemperature, followed by the addition of the alkyl halide.

In FIG. 28, the synthesis of compounds of Formula V is depicted, where Xis N. The conversion of chloride 79 to compounds 61, where R⁹=aryl,heteroaryl, alkyl, cycloalkyl, alkenyl, alkynyl, amino or aniline, canbe achieved using palladium-mediated cross-coupling conditions. Ingeneral, this chemistry can be accomplished using a wide variety of Pdcatalysts and ligands, with or without added base, in a suitable organicsolvent such as DMF, PhMe. DME, THF, CH₃CN at elevated temperature. Thecoupling partner will depend on the nature of R⁹. Thesepalladium-mediated cross couplings are well documented in the literatureand are known by anyone skilled in the art. When R⁹ is alkenyl oralkynyl, these can be further reduced using the appropriate reducingagent to provide alkyl substituents at R⁹.

FIGS. 29-32 depict the synthesis of compounds of Formula V, where X isN. In these syntheses, aldehyde 61 (R⁹=—C(O)H) is converted to variousother functionalities. FIG. 29 depicts the conversion of aldehyde 61 toamine 80. This can be accomplished by reductive amination, whichinvolves the reaction of the aldehyde with the desired amine and AcOH,followed by reduction with a suitable reducing agent, including but notlimited to ME₄NBH(OAc)₃, in a suitable organic solvent such as CH₃CN atambient temperature. Carboxylic acid 62, as well as hydroxamate 63 andamide 64, where R⁹ is equal to CH₂NR³R⁴, can then be prepared from 80 asdescribed in FIGS. 19 and 20.

FIG. 30 depicts the conversion of aldehyde 61 (R⁹=—C(O)H) to alcohol 81and ether 82. Reduction of aldehyde 61 (R⁹=—C(O)H) with a suitablereducing agent, including but not limited to NaBH₄ provides alcohol 81.Alcohol 81 can be converted to ether 82 by reaction with a suitable baseand the desired alkyl halide, including but not limited to addition ofNaH to alcohol 81, followed by the addition of an alkyl bromide or alkyliodide. Alcohol 81 can also be converted to ether 82 by halogenation oractivation followed by addition of a desired alcohol. Halogenation canbe accomplished with POCl₃, thionyl chloride, oxalyl chloride, PCl₅,PBr₃, or Ph₃P and Br₂, and activation can be achieved by reaction ofaldehyde 61 (R⁹=—C(O)H) with, for example, MsCl or TsCl. Both thehalogenation and activation steps are followed by addition of a desiredalcohol to yield 82. Carboxylic acid 62, as well as hydroxamate 63 andamide 64. R⁹ is —CH₂OH or —CH₂OR, can then be prepared from 81 or 82 asdescribed in FIGS. 19 and 20.

FIG. 31 depicts the conversion of aldehyde 61 (R⁹=—C(O)H) to amide 84.Oxidation of aldehyde 61 (R⁹=—C(O)H) with a suitable oxidizing agent,such as but not limited to KMnO₄, CrO₃ or Na₂Cr₂O₇, provides carboxylicacid 83. Conversion of acid 83 to amide 84 can be accomplished usingstandard coupling procedures, including but not limited to EDCl, HOBt,or PyBOP and the appropriate amine in suitable organic solvents such asDMF, THF, or methylene chloride. In some instances, the amine used inthe coupling reaction contains a standard protecting group. In thosecases, the protecting group can be removed by standard conditions knownin the art. Carboxylic acid 62, as well as hydroxamate 63 and amide 64,where R⁹=—C(O)NR³R⁴, can then be prepared from 84 as described in FIGS.19 and 20.

FIG. 32 depicts the conversion of aldehyde 61 (R⁹=—C(O)H) to alkyl 85.Reaction of aldehyde 61 (R⁹=C(O)H) under standard Wittig reactionconditions, followed by reduction of the resulting alkene provides alkyl85. The Wittig reaction involves the addition of a desired phosphorousylide, R₂C—P(C₆H₅)₃, to the aldehyde in a suitable organic solvent suchas THF. The conditions for formation of the desired phosphorous ylideare well documented in the literature and are known by anyone skilled inthe art. Reduction of the alkene to provide 85 can be accomplished undera hydrogen atmosphere with a suitable catalyst, such as PtO₂ or Pd/C.Carboxylic acid 62, as well as hydroxamate 63 and amide 64, where R9 isequal to CH₂CR₂, can then be prepared from 85 as described in FIGS. 19and 20.

In FIG. 33, the synthesis of compounds of Formula V is depicted where Wis heterocyclic. Carboxylic acid 55 or 62 can be converted to hydrazide86 using standard coupling procedures, including but not limited toEDCl, HOBt, or PyBOP and hydrazine in suitable organic solvents such asDMF, THF, or methylene chloride. Hydrazide 86 can then be converted toseveral desired heterocyclic analogs by cyclizaiion with an appropriatereagent. Conversion of 86 to amino oxadiazole 87 can be accomplishedusing cyanogen bromide and a base such as NaHCO₃, in a suitable biphasicsolvent system such as dioxane and water at room temperature. Conversionof 86 to the oxadiazolone 88 can be accomplished by reaction withphosgene, CDI, or a phosgene equivalent. Conversion of 86 the aminotriazole 89 can be accomplished in a two-step procedure, first byreaction with NH₃CN and aqueous HCl, followed by cyclization withtriphenylphosphine, triethylamine and carbon tetrachloride. Conversionof 86 to the methyl trizole 90 can be accomplished in a two Stepprocedure, first by reaction with an appropriate coupling agent such ascyanamide or ethyl acetimidate, followed by cyclization withtriphenylphosphine, triethylamine and carbon tetrachloride indichloromethane. Finally, conversion of carboxylic acid 55 or 62 to theaminothiazole 91 can be accomplished with thiosemicarbazide usingstandard coupling reagents, such as EDCl, followed by cyclization withtriphenylphosphine, triethylamine and carbon tetrachloride indichloromethane.

In FIG. 34, the synthesis of compounds of Formula V is depicted where Wis heterocyclic. Ring opening of oxadiazolone 88 with a desired amine isaccomplished in EtOH under refluxing conditions to yield 92, which canbe recyclized to 93 with triphenylphosphine, triethylamine and carbontetrachloride in dichloromethane. In some instances, the amine used inthe ring-opening reaction contains a standard protecting group. In thosecases, the protecting group can be removed by standard conditions knownin the art.

The preparation of compounds of the Formula I wherein X=N and R⁹ is H orBr is depicted in FIG. 35. Substituted hydrazine 28 can be converted tohydrazono propanoate 29 by a two-step procedure. In the first step,hydrazine 28 is condensed with ethyl pyruvate under standard dehydratingconditions such as in the presence of MgSO₄ in a suitable organicsolvent such as chloroform or methylene chloride al temperatures rangingfrom 0° C. to ambient. In the second step, acylation is achieved bytreatment with base at low temperature in a suitable organic solventsuch as THF, DMF, dioxane or MeCN, followed by the addition of methylmalonyl chloride. In one embodiment, the hydrazone is treated with LiHin THF at 0° C. followed by the addition of methyl malonyl chloride andwarming to room temperature. Hydroxy pyridazinone 31 is prepared fromhydrazono propanoate 29 by cyclization under strongly basic conditionsfollowed by decarboxylation. The cyclization can be accomplished bytreatment of hydrazono propanoate 29 with a strong base such as DBU, LDAor NaH in a suitable organic solvent such as THF or MeCN at roomtemperature. In one embodiment, cyclization is achieved with DBU in MeCNat room temperature. Decarboxylation to form hydroxypyridazinone 31 canbe achieved by healing the methyl ester pyrazinone moiety in a suitableorganic solvent such as dioxane or decalin or dioxane/decalin mixture tohigh temperatures in the presence of concentrated HCl. Carboxylic acid94 can be prepared from hydroxy pyridazinone 31 in a two-step process,i.e. chlorination followed by oxidation. The chlorination step can beachieved by treatment with POCl₃, thionyl chloride, oxalyl chloride orPCl₅. In one embodiment, this transformation is achieved with POCl₃ neatat elevated temperature (˜85° C.). Following the chlorination step,carboxylic acid 94 can be prepared by oxidation under standardconditions including but not limited to KMnO₄ in water. SeO₂ in organicsolvent such as dioxane, xylene, or pyridine. NaOCl/RuCl₃, CrO₃ inaqueous H₂SO₄, K₂Cr₂O₇, and Na₂Cr₂O₇ in water. In one embodiment thistransformation is achieved with K₂Cr₂O₇—H₂SO₄. Carboxylic acid 94 can beconverted to pyridazinone ester 95 in a two-step procedure whichincludes esterification of pyridazinone acid 94 followed by apalladium-mediated cross-coupling reaction. The esterification can beperformed under standard conditions including, but not limited to,concentrated HCl in MeOH, TMSCl in MeOH or TMSCHN₂ in suitable organicsolvents such as ether/MeOH. THF/MeOH or PhMe/MeOH. Thepalladium-mediated cross-coupling reaction can be achieved by standardmethods including, but not limited to, treating the chloropyridazinoneester with an aniline, a palladium catalyst such as Pd(OAc)₂,PdCl₂(dppf), Pd(Ph₃P)₄, or Pd₂dba₃, a phosphine ligand and a base in asuitable organic solvent such as THF, DMF, PhMe, DME or MeCN at elevatedtemperature. In one embodiment, the cross-coupling reaction comprisestreating the ester 94 with Pd(OAc)₂,rac-2,2-bis(diphenylphosphino)-1,1′-binaphthyl and Cs₂CO₃ in toluene at70 to 100° C. In embodiments of compound 95 where R⁹=Br is desired, thebromine substituent can be incorporated after the cross-couplingreaction. Bromination of pyridazinone can be accomplished with NBS in asuitable organic solvent such as DMF, MeCN or mixed solvent systems atroom temperature. In one embodiment the bromination is carried out inDMF. Hydroxamate 96 can be prepared by treating pyridazinone ester 95with the appropriate hydroxylamine and amide base such as LDA, LiHMDS orNaHMDS in a suitable organic solvent such as THF at low temperature. Inone embodiment, a LiHMDS solution is added to a solution of pyridazinoneester 95 and hydroxylamine in THF at 0° C. The reaction mixture is thenwarmed to room temperature to yield the desired hydroxamate 96. In someinstances, the hydroxylamine used in the coupling reaction contains astandard protecting group. In those cases, the protecting group can beremoved by standard conditions known in the art.

FIG. 36 outlines the synthesis of compounds of Formula I wherein X=N andR⁹ is halogen or alkyl. Substituted hydrazine 28 can be converted tohydrazono malonate 97 according to one of two procedures. In oneembodiment, condensation of substituted hydrazine 28 followed byacylation is particularly useful for analogs where R⁹ is alkyl orhalogen. In this embodiment, hydrazine 28 can be condensed with diethyl2-oxomalonate under standard dehydrating conditions using a Dean-Starktrap in a suitable organic solvent such as benzene or toluene altemperatures ranging from 80 to 120° C. Acylation with a reagent thatdelivers an acyl group to provide the hydrazono malonate 97 is achievedby treatment with base at the appropriate temperature in a suitableorganic solvent such as THF, DMF, dioxane or MeCN followed by theaddition of the acylating reagent. Examples of acylating reagents arewell known to persons skilled in the art and include, but are notlimited to, acid chlorides, acid anhydrides, and activated esters. Inone embodiment, the hydrazone is treated with LiH in THF at 0° C.followed by the addition of an acid chloride and stirred at 25 to 60° C.to provide compound 97. An alternative method for synthesizing compound97 wherein R⁹ is not halogen involves acylating the hydrazine 28 with areagent that delivers an acyl group, followed by condensation withdiethyl 2-oxomalonate to provide the hydrazono malonate 97. According tothis method, the substituted hydrazine 28 can be converted to thehydrazide by standard acylation methods. In one embodiment thistransformation is achieved with the appropriate acid chloride inmethylene chloride at 0° C. to ambient temperature. The hydrazideobtained is condensed with diethyl ketomalonate under standarddehydrating conditions using a Dean-Stark trap in a suitable organicsolvent such as benzene or toluene at temperature from 80 to 130° C.Pyridazinone 99 is prepared from hydrazono malonate 97 by cyclizationunder basic conditions to provide the intermediated acid or ester 98,followed by chlorination to provide the pyridazinone 99. The cyclizationcan be accomplished by treatment of hydrazono malonate 7 with an amidebase such as LiHMDS, NaHMDS, KHMDS or LDA in a suitable organic solventsuch as THF or ether at low temperature. In one embodiment, cyclizationis achieved with LiHMDS in THF at low temperature (−78 to −40° C.),followed by treatment with concentrated HCl to yield the esterderivative of 98 (R=Et). In another embodiment, the acid derivative of98 (R=H) is obtained by in-situ saponification of the pyridazinone ester98. Upon completion of cyclization, the reaction mixture is quenchedwith water at low temperatures (−78 to −40° C.), then warmed to ambienttemperature with stirring followed by acidification. Pyridazinone 99 isthen prepared from pyridazinone acid or ester 98 by treatment withPOCl₃, thionyl chloride, oxalyl chloride or PCl₅. In one embodiment thistransformation is achieved with POCl₃ neat at elevated temperature (˜85°C.). When R⁹ is not F, pyridazinone acid 99 (when R= H) can then beconvened to pyridazinone 101. Incorporation of the aniline moiety isaccomplished by an S_(N)Ar reaction in a suitable organic solvent suchas THF using an amide base such as LDA, LiHMDS, NaHMDS or KHMDS atappropriate temperatures (−78° C. to room temperature). In oneembodiment, the aniline is added to LDA or LiHMDS in THF al lowtemperature (−20 to −80° C.). The pyridazinone acid 99 (R=H) is thenadded and the reaction mixture is warmed to room temperature to generatecarboxylic acid 101. Hydroxamates 96 and amides 102 can then be preparedfrom acid 101 using standard coupling reagents including, but notlimited to, EDCl, HOBt, or PyBOP and the appropriate amine orhydroxylamine in a suitable organic solvent such as DMF. THF ormethylene chloride. In some instances, the amine or hydroxylaminecontains a standard protecting group. In those cases, the protectinggroup can be removed by standard conditions known in the art.Alternatively, ester pyridazinone 99 (R=Et) can be converted tohydroxamate 96 through pyridazinone ester 100 by the standard methodsdescribed in FIG. 35. When R⁸= Br or I is desired, the desired halogencan be incorporated using NBS or NIS in a suitable organic solvent ormixed solvent system such as DMF, THF-MeOH, or AcOH-THF in the presenceof an appropriate acid catalyst.

In FIG. 37, the synthesis of compounds of Formula V where X= N andR⁹=aryl, heteroaryl, alkyl, cycloalkyl, alkenyl, alkynyl, cyano, aminoor anilino is shown, in which 2,6-dichloro-nicotinic acid is used as thestarting material. The nicotinic acid 103 is converted to the monochloro acid 104 by refluxing in 2 N aqueous NaOH following the proceduredescribed in U.S. Pat. No. 3,682,932. Alkylation of 104 to provide 105can be achieved by standard basic alkylation conditions incorporatingalkyl halides, with two equivalents of the appropriate alkyl halide andbase to give a mixture of the N-alkyl pyridone ester 105 and theregioisomeric O-alkyl pyridine ester, which are easily separated bycolumn chromatography. These conditions include, but are not limited to,K₂CO₃ in acetone or DMF at room or elevated temperature or NaH in THF atambient or elevated temperature and then addition of the alkyl halide.In certain embodiments this alkylation is achieved with LiH in DMF at 0°C. followed by addition of alkyl bromide or alkyl iodide and warming toroom temperature. Bromination of pyridone ester 105 can be accomplishedwith either Br₂ and acetic acid or NBS in a suitable organic solventsuch as DMF. In certain embodiments NBS is added to a solution ofpyridone ester 105 in DMF to yield 106. Conversion of bromide 106 tocompound 107 can be achieved using Pd mediated cross couplingconditions. When R⁹=alkenyl or alkynyl, these can be further reducedusing the appropriate reducing agent to provide alkyl substituents atR⁹. In general, this chemistry can be accomplished using a wide varietyof Pd catalysts and ligands, with or without added base, in a suitableorganic solvent such as DMF, PhMe, DME, THF, CH₃CN at elevatedtemperature. The coupling partner will depend on the nature of R⁹. Forexample, if R⁹=CN is desired, the coupling partner is Zn(CN)₂. Thisreaction can be carried out with Pd₂dba₃, and dppf in NMP at 120° C.These palladium-mediated cross couplings are well documented in theliterature and are well known to one skilled in the art. Incorporationof the properly substituted aniline moiety to provide 108 isaccomplished by S_(N)AR reaction. This can be done in a suitable organicsolvent such as THF using an amide base such as LDA, LiHMDS, NaHMDS, orKHMDS at appropriate temperatures (−78° C. to room temperature). Incertain embodiments the aniline is added to LDA or LiHMDS in THF at lowtemperature (−20 to −80° C.). The pyridone 105 is then added and themixture is stirred at low temperature to generate ester 108. Carboxylicacid 109 can then be prepared using standard saponification conditionssuch as LiOH or NaOH in standard mixed aqueous/organic solvent systems.Hydroxamate 110 and amide 111 can be prepared using standard couplingprocedures, including but not limited to EDCl, HOBt, or PyBOP and theappropriate amine or hydroxylamine in suitable organic solvents such asDMF, THF, or methylene chloride. In certain embodiments, the coupling isaccomplished with HOBt and EDCl in DMF. In some instances, the amine orhydroxylamine used in the coupling reaction contains a standardprotecting group. In those cases, the protecting group can be removed bystandard conditions known in the art.

In FIG. 38, an alternative synthesis of compounds of Formula V where X=Nand R⁹=aryl, heteroaryl, alkyl, cycloalkyl, alkenyl, alkynyl, cyano,amino or anilino is depicted, in which 2,6-dichloro-nicotinic acid isused as the starting material. This route is particularly useful foranalogs where R⁷ is not equal to Me or Et. Nicotinic acid 103 can beconverted to the N-alkyl pyridone methyl ester 114 following a sevenstep procedure, where 2,6-dichloro-nicotinic acid 103 is first convenedto the methoxy pyridine acid, which is esterified to give the methylester and then deprotected to yield the mono chloro ester 112. Incertain embodiments the conversion to the methoxy pyridine acid iscarried out by adding potassium t-butoxide to a solution of the acid 103in MeOH and this mixture is then heated to reflux for several days.Esterification to give the methyl ester can be carried out understandard conditions, including but not limited to Fisher esterification(MeOH, H2SO₄), TMSCl in MeOH or TMSCHN₂ in suitable organic solventssuch as PhMe/MeOH. Demethylation of the methoxy pyridine can then beaccomplished by standard conditions including but not limited to HCl atelevated temperature, pTsOH in acetic acid at elevated temperature andaqueous HBr in MeOH at elevated temperature. Preferable demethylation togive pyridone 112 is achieved by treatment of the methoxy pyridine withaqueous HBr in acetic acid at elevated temperature (80 to 120° C.).Alkylation of 112 can be achieved by standard basic alkylationconditions incorporating alkyl halides, with one equivalent of theappropriate alkyl halide and base to give a mixture of the N-alkylpyridone ester 113 and the regioisomeric O-alkyl pyridine ester, whichare easily separated by column chromatography. These conditions includebut are not limited to K₂CO₃ in acetone or DMF at room or elevatedtemperature or NaH in THF at ambient or elevated temperature and thenaddition of the alkyl halide. In certain embodiments this alkylation isachieved with LiH in DMF at 0° C., followed by addition of alkyl bromideor alkyl iodide and wanning to room temperature. Bromination of pyridoneester 113 can be accomplished with either Br₂ and acetic acid or NBS ina suitable organic solvent such as DMF. In certain embodiments NBS isadded to a solution of pyridone ester 113 in DMF to yield 114.Conversion of bromide 114 to compound 115 can be achieved usingpalladium-mediated cross-coupling conditions. When R⁹=alkenyl oralkynyl, these can be further reduced using the appropriate reducingagent to provide alkyl substituents at R⁹. In general, this chemistrycan be accomplished using a wide variety of Pd catalysts and ligands,with or without added base, in a suitable organic solvent such as DMF,PhMe, DME, THF, CH₃CN at elevated temperature. The coupling partner willdepend on the nature of R⁹. These Pd mediated cross-couplings are welldocumented in the literature and are well known to one skilled in theart. Incorporation of the properly substituted aniline moiety to provide116 is accomplished by S_(N)AR reaction. This can be done in a suitableorganic solvent such as THF using an amide base such as LDA, LiHMDS,NaHMDS, or KHMDS at appropriate temperatures (−78° C. to roomtemperature). In certain embodiments the aniline is added to LDA orLiHMDS in THF at low temperature (−20 to −80° C.). The pyridone 115 isthen added and the mixture is stirred at low temperature to generateester 116. Conversion of 116 to carboxylic acid 109, as well ashydroxamate 110 and amide 111 can be accomplished as described for FIG.37. Alternatively, hydroxamate 110 can be prepared directly from methylester 116 in a suitable organic solvent such as THF using theappropriate hydroxylamine and amide base such as LDA, LiHMDS, NaHMDS, orKHMDS at appropriate temperatures (−78° C. to room temperature). Incertain embodiments, a solution of LiHMDS is added to a solution of theester 116 and the hydroxylamine in THF at 0° C. The reaction mixture isthen warmed to room temperature to yield the desired hydroxamate 110. Insome instances, the hydroxylamine used in the coupling reaction containsa standard protecting group. In those cases, the protecting group can beremoved by standard conditions known in the art.

In FIG. 39, the synthesis of compounds of Formula V where X=N and R⁹=Clis depicted, in which N-alkyl pyridone methyl ester 112 is used as thestarling material. Formation of 117 can be accomplished by incorporationof the properly substituted aniline moiety by S_(N)AR reaction. This canbe done in a suitable organic solvent such as THF using an amide basesuch as LDA, LiHMDS, NaHMDS, or KHMDS al appropriate temperatures (−78°C. to room temperature). In certain embodiments the aniline is added toLDA or LiHMDS in TIIF at low temperature (−20 to −80° C.). The pyridone112 is then added and the mixture is stirred at low temperature togenerate ester 117. This can be done in a suitable organic solvent suchas THF using an amide base such as LDA, LiHMDS, NaHMDS, or KHMDS atappropriate temperatures (−78° C. to room temperature). Chlorination ofpyridone 117 to give pyridone 118 can be accomplished using standardconditions such as NCS in a suitable organic solvent, such as DMF.Conversion of 118 to carboxylic acid 119, as well as hydroxamate 120 andamide 121 can be accomplished as described for FIGS. 37 and 38.

FIG. 40 illustrates the synthesis of compounds of Formula I whereinR⁹=F. 4-Fluoropyridazinone 123 can be prepared from 4-chloropyridazinone122 by treatment with KF or HF with or without base such as Et₃N or Me₃Nin suitable organic solvents such as CH₃CN, THF, DMF, NMP or DMSO. Inone embodiment, this transformation is achieved with KF in DMSO atelevated temperature (e.g. 160° C.). Pyridazinone ester 123 (when R=Et)can be converted to pyridazinone 124, wherein incorporation of theaniline moiety is accomplished by SnAr reaction. This can be done in asuitable organic solvent such as DMF, EtOH, iPrOH, CH₃CN or THF using abase such as Cs₂CO₃, NaHCO₃, K₂CO₃ or Na₂CO₃ at temperature from 80 to160° C. In one embodiment, the aniline and Cs₂CO₃ are added to asolution of pyridazinone 123 in DMF and the reaction mixture is heatedto 80° C. Alternatively, pyridazinone acid 123 (R= H) can be convertedto pyridazinone 125 by standard methods such as those described in FIG.36. Pyridazinone 124 or 125 can be converted to hydroxamates or amidesas described in FIG. 35 or 36.

In FIG. 41, the synthesis of compounds of Formula I where R⁹=CN and R¹,R² or R⁸ do not equal Br or I is depicted, in which pyridone methylester 117 is used as the starting material. Bromination of pyridoneester 117 can be accomplished with either Br₂ and acetic acid or NBS ina suitable organic solvent such as DMF. Preferably NBS is added to asolution of pyridone ester 117 in DMF to yield 126. Conversion ofbromide 126 to compound 127 where R⁹ is cyano can be achieved using Pdmediated cross coupling conditions. In general, this chemistry can beaccomplished using a wide variety of Pd catalysts and ligands, with orwithout added base, in a suitable organic solvent such as DMF, PhMe,DME, THF, CH₃CN or NMP at elevated temperature. Preferably, thisreaction is carried out with Zn(CN)₂ and Pd₂dba₃ and dppf in DMF at 120°C. Conversion of 127 to carboxylic acid 128, as well as hydroxamate 129and amide 130 can be accomplished as described for FIGS. 37 and 38.

The invention also relates to a pharmaceutical composition for thetreatment of a hyperproliferative disorder in a mammal which comprises atherapeutically effective amount of a compound of the present invention,or a pharmaceutically acceptable salt, prodrug or hydrate thereof, and apharmaceutically acceptable carrier. In one embodiment, saidpharmaceutical composition is for the treatment of cancer such as brain,lung, squamous cell, bladder, gastic, pancreatic, breast, head, neck,renal, kidney, ovarian, prostate, colorectal, esophageal, testicular,gynecological or thyroid cancer. In another embodiment, saidpharmaceutical composition is for the treatment of a non-canceroushyperproliferative disorder such as benign hyperplasia of the skin(e.g., psoriasis), restenosis, or prostate (e.g., benign prostatichypertrophy (BPH)).

The invention also relates to a pharmaceutical composition for thetreatment of pancreatitis or kidney disease (including proliferativeglomerulonephritis and diabetes-induced renal disease) or the treatmentof pain in a mammal which comprises a therapeutically effective amountof a compound of the present invention, or a pharmaceutically acceptablesalt, prodrug or hydrate thereof, and a pharmaceutically acceptablecarrier.

The invention also relates to a pharmaceutical composition for theprevention of blastocyte implantation in a mammal which comprises atherapeutically effective amount of a compound of the present invention,or a pharmaceutically acceptable salt, prodrug or hydrate thereof, and apharmaceutically acceptable carrier.

The invention also relates to a pharmaceutical composition for treatinga disease related to vasculogenesis or angiogenesis in a mammal whichcomprises a therapeutically effective amount of a compound of thepresent invention, or a pharmaceutically acceptable salt, prodrug orhydrate thereof, and a pharmaceutically acceptable carrier. In oneembodiment, said pharmaceutical composition is for treating a diseaseselected from the group consisting of tumor angiogenesis, chronicinflammatory disease or other inflammatory condition such as rheumatoidarthritis, atherosclerosis, inflammatory bowel disease, skin diseasessuch as psoriasis, eczema, and scleroderma, diabetes, diabeticretinopathy, retinopathy of prematurity, age-related maculardegeneration, hemangioma, glioma, melanoma, Kaposi's sarcoma andovarian, breast, lung, pancreatic, prostate, colon and epidermoidcancer.

The invention also relates to a method of treating a hyperproliferativedisorder in a mammal that comprises administering to said mammal atherapeutically effective amount of a compound of the present invention,or a pharmaceutically acceptable salt, prodrug or hydrate thereof. Inone embodiment, said method relates to the treatment of cancer such asbrain, lung, squamous cell, bladder, gastic, pancreatic, breast, head,neck, renal, kidney, ovarian, prostate, colorectal, esophageal,testicular, gynecological or thyroid cancer. In another embodiment, saidmethod relates to the treatment of a non-cancerous hyperproliferativedisorder such as benign hyperplasia of the skin (e.g., psoriasis),restenosis, or prostate (e.g., benign prostatic hypertrophy (BPH)).

The invention also relates to a method for the treatment of ahyperproliferative disorder in a mammal that comprises administering tosaid mammal a therapeutically effective amount of a compound of thepresent invention, or a pharmaceutically acceptable salt, prodrug orhydrate thereof, in combination with an anti-tumor agent selected fromthe group consisting of mitotic inhibitors, alkylating agents,anti-metabolites, intercalating antibiotics, growth factor inhibitors,cell cycle inhibitors, enzyme inhibitors, topoisomerase inhibitors,biological response modifiers, anti-hormones, angiogenesis inhibitors,and anti-androgens.

The invention also relates to a method of treating pancreatitis orkidney disease in a mammal that comprises administering to said mammal atherapeutically effective amount of a compound of the present invention,or a pharmaceutically acceptable salt, prodrug or hydrate thereof.

The invention also relates to a method of preventing blastocyteimplantation in a mammal that comprises administering to said mammal atherapeutically effective amount of a compound of the present invention,or a pharmaceutically acceptable salt, prodrug or hydrate thereof.

The invention also relates to a method of treating diseases related tovasculogenesis or angiogenesis in a mammal that comprises administeringto said mammal a therapeutically effective amount of a compound of thepresent invention, or a pharmaceutically acceptable salt, prodrug orhydrate thereof. In one embodiment, said method is for treating adisease selected from the group consisting of tumor angiogenesis,chronic inflammatory disease such as rheumatoid arthritis,atherosclerosis, inflammatory bowel disease, skin diseases such aspsoriasis, eczema, and scleroderma, diabetes, diabetic retinopathy,retinopathy of prematurity, age-related macular degeneration,hemangioma, glioma, melanoma, Kaposi's sarcoma, and ovarian, breast,lung, pancreatic, prostate, colon and epidermoid cancer.

The invention also relates to a pharmaceutical composition for treatinga disease or condition related to inflammatory disease, autoimmunedisease, destructive bone disorders, proliferative disorders, infectiousdisease, viral disease, fibrotic disease or neurodegenerative disease ina mammal which comprises a therapeutically effective amount of acompound of the present invention, or a pharmaceutically acceptablesalt, prodrug or hydrate thereof, and a pharmaceutically acceptablecarrier. Examples of the above diseases and/or conditions include but isnot limited to rheumatoid arthritis, atherosclerosis, inflammatory boweldisease, skin diseases such as psoriasis, eczema, and scleroderma,diabetes and diabetic complications, diabetic retinopathy, retinopathyof prematurity, age-related macular degeneration, hemangioma, chronicobstructive pulmonary disease, idiopathic pulmonary fibrosis, allergicresponses including asthma allergic rhinitis and atopic dermatitis,renal disease and renal failure, polycystic kidney disease, acutecoronary syndrome, congestive heart failure, osteoarthritis,neurofibromatosis, organ transplant rejection, cachexia and pain.

Further provided is a compound of Formula I, Formula II, Formula III,Formula IV or Formula V for use as a medicament in the treatment of thediseases and conditions described above in a warm-blooded animal,preferably a mammal, more preferably a human, suffering from suchdisorder. Also provided is the use of a compound of Formula I, FormulaII, Formula III, Formula IV or Formula V in the preparation of amedicament for the treatment of the diseases and conditions describedabove in a warm-blooded animal, preferably a mammal, more preferably ahuman, suffering from such disorder.

Patients that can be treated with compounds of the present invention, orpharmaceutically acceptable salts, prodrugs and hydrates of saidcompounds, according to the methods of this invention include, forexample, patients that have been diagnosed as having psoriasis,restenosis, atherosclerosis, BPH, lung cancer, bone cancer. CMML,pancreatic cancer, skin cancer, cancer of the head and neck, cutaneousor intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer,cancer of the anal region, stomach cancer, colon cancer, breast cancer,testicular, gynecologic tumors (e.g., uterine sarcomas, carcinoma of thefallopian tubes, carcinoma of the endometrium, carcinoma of the cervix,carcinoma of the vagina or carcinoma of the vulva), Hodgkin's disease,cancer of the esophagus, cancer of the small intestine, cancer of theendocrine system (e.g., cancer of the thyroid, parathyroid or adrenalglands), sarcomas of soft tissues, cancer of the urethra, cancer of thepenis, prostate cancer, chronic or acute leukemia, solid tumors ofchildhood, lymphocytic lymphomas, cancer of the bladder, cancer of thekidney or ureter (e.g., renal cell carcinoma, carcinoma of the renalpelvis), or neoplasms of the central nervous system (e.g., primary CNSlymphoma, spinal axis tumors, brain stem gliomas or pituitary adenomas).

This invention also relates to a pharmaceutical composition forinhibiting abnormal cell growth in a mammal which comprises an amount ofa compound of the present invention, or a pharmaceutically acceptablesalt or solvate or prodrug thereof, in combination with an amount of achemotherapeutic, wherein the amounts of the compound, salt, solvate, orprodrug, and of the chemotherapeutic are together effective ininhibiting abnormal cell growth. Many chemotherapeutics are presentlyknown in the art. In one embodiment, the chemotherapeutic is selectedfrom the group consisting of mitotic inhibitors, alkylating agents,anti-metabolites, intercalating antibiotics, growth factor inhibitors,cell cycle inhibitors, enzymes, topoisomerase inhibitors, biologicalresponse modifiers, anti-hormones, angiogenesis inhibitors, andanti-androgens.

This invention further relates to a method for inhibiting abnormal cellgrowth in a mammal or treating a hyperproliferative disorder whichmethod comprises administering to the mammal an amount of a compound ofthe present invention, or a pharmaceutically acceptable salt or solvateor prodrug thereof, in combination with radiation therapy, wherein theamounts of the compound, salt, solvate, or prodrug, is in combinationwith the radiation therapy effective in inhibiting abnormal cell growthor treating the hyperproliferative disorder in the mammal. Techniquesfor administering radiation therapy are known in the art, and thesetechniques can be used in the combination therapy described herein. Theadministration of the compound of the invention in this combinationtherapy can be determined as described herein.

It is believed that the compounds of the present invention can renderabnormal cells more sensitive to treatment with radiation for purposesof killing and/or inhibiting the growth of such cells. Accordingly, thisinvention further relates to a method for sensitizing abnormal cells ina mammal to treatment with radiation which comprises administering tothe mammal an amount of a compound of the present invention orpharmaceutically acceptable salt or solvate or prodrug thereof, whichamount is effective is sensitizing abnormal cells to treatment withradiation. The amount of the compound, salt, or solvate in this methodcan be determined according to the means for ascertaining effectiveamounts of such compounds described herein.

The invention also relates to a method of and to a pharmaceuticalcomposition of inhibiting abnormal cell growth in a mammal whichcomprises an amount of a compound of the present invention, or apharmaceutically acceptable salt or solvate thereof, a prodrug thereof,or an isotopically-labeled derivative thereof, and an amount of one ormore substances selected from anti-angiogenesis agents, signaltransduction inhibitors, and antiproliferative agents.

Anti-angiogenesis agents, such as MMP-2 (matrix-metalloprotienase 2)inhibitors, MMP-9 (matrix-metalloprotienase 9) inhibitors, and COX-II(cyclooxygenase II) inhibitors, can be used in conjunction with acompound of the present invention and pharmaceutical compositionsdescribed herein: Examples of useful COX-II inhibitors include CELEBREX™(alecoxib), valdecoxib, and rofecoxib. Examples of useful matrixmetalloprotienase inhibitors are described in WO 96/33172, WO 96/27583,EP 818442, EP 1004578, WO 98/07697, WO 98/03516, WO 98/34918, WO98/34915, WO 98/33768, WO 98/30566, EP 606,046, EP 931,788. WO 90/05719.WO 99/52910, WO 99/52889, WO 99/29667, WO 99/07675, EP 945864, U.S. Pat.Nos. 5,863,949, 5,861,510, and EP 780,386, all of which are incorporatedherein in their entireties by reference. Preferred MMP-2 and MMP-9inhibitors are those that have little or no activity inhibiting MMP-1.More preferred, are those that selectively inhibit MMP-2 and/or MMP-9relative to the other matrix-metalloproteinases (i.e., MMP-1, MMP-3,MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP-11, MMP-12, and MMP-13).

The terms “abnormal cell growth” and “hyperproliferative disorder” areused interchangeably in this application.

“Abnormal cell growth.” as used herein, unless otherwise indicated,refers to cell growth that is independent of normal regulatorymechanisms (e.g., loss of contact inhibition). This includes, forexample, the abnormal growth of: (1) tumor cells (tumors) thatproliferate by expressing a mutated tyrosine kinase or over-expressionof a receptor tyrosine kinase; (2) benign and malignant cells of otherproliferative diseases in which aberrant tyrosine kinase activationoccurs; (3) any tumors that proliferate by receptor tyrosine kinases;(4) any tumors that proliferate by aberrant serine/threonine kinaseactivation; and (5) benign and malignant cells of other proliferativediseases in which aberrant serine/theroine kinase activation occurs.

The term “treating.” as used herein, unless otherwise indicated, meansreversing, alleviating, inhibiting the progress of, or preventing thedisorder or condition to which such term applies, or one or moresymptoms of such disorder or condition. The term “treatment.” as usedherein, unless otherwise indicated, refers to the act of treating as“treating” is defined immediately above.

The amount of a given agent that will correspond to such an amount willvary depending upon factors such as the particular compound, diseasecondition and its severity, the identity (e.g., weight) of the mammal inneed of treatment, but can nevertheless be routinely determined by oneskilled in the art. “Treating” is intended to mean at least themitigation of a disease condition in a mammal, such as a human, that isaffected, at least in part, by the activity of MEK, and includes, but isnot limited to preventing the disease condition from occurring in amammal, particularly when the mammal is found to be predisposed tohaving the disease condition but has not yet been diagnosed as havingit; modulating and/or inhibiting the disease condition; and/oralleviating the disease condition.

In order to use a compound of the Formula I-V or a pharmaceuticallyacceptable salt or prodrug thereof, for the therapeutic treatment(including prophylactic treatment) of mammals including humans, it isnormally formulated in accordance with standard pharmaceutical practiceas a pharmaceutical composition. According to this aspect of theinvention there is provided a pharmaceutical composition that comprisesa compound of the Formula I-V, or a pharmaceutically acceptable salt orprodrug thereof, as defined hereinbefore in association with apharmaceutically acceptable diluent or carrier.

To prepare the pharmaceutical compositions according to one embodimentof this invention, a therapeutically or prophylactically effectiveamount of a compound of Formula I-V or a pharmaceutically acceptablesalt, solvate, metabolite or prodrug thereof (alone or together with anadditional therapeutic agent) is intimately admixed with apharmaceutically acceptable carrier according to conventionalpharmaceutical compounding techniques to produce a dose. A carrier maytake a wide variety of forms depending on the form of preparationdesired for administration, e.g., oral or parenteral. Examples ofsuitable carriers include any and all solvents, dispersion media,adjuvants, coatings, antibacterial and antifungal agents, isotonic andabsorption delaying agents, sweeteners, stabilizers (to promote longterm storage), emulsifiers, binding agents, thickening agents, salts,preservatives, solvents, dispersion media, coatings, antibacterial andantifungal agents, isotonic and absorption delaying agents, flavoringagents, and miscellaneous materials such as buffers and absorbents thatmay be needed in order to prepare a particular therapeutic composition.The use of such media and agents with pharmaceutically active substancesis well known in the art. Except insofar as any conventional media oragent is incompatible with a compound of Formula I-V, its use in thetherapeutic compositions and preparations is contemplated. Supplementaryactive ingredients can also be incorporated into the compositions andpreparations as described herein,

The compositions of the invention may be in a form suitable for oral use(for example as tablets, lozenges, hard or soft capsules, aqueous oroily suspensions, emulsions, dispersible powders or granules, syrups orelixirs), for topical use (for example as creams, ointments, gels, oraqueous or oily solutions or suspensions), for administration byinhalation (for example as a finely divided powder or a liquid aerosol),for administration by insufflation (for example as a finely dividedpowder) or for parenteral administration (for example as a sterileaqueous or oily solution for intravenous, subcutaneous, or intramusculardosing or as a suppository for rectal dosing). For example, compositionsintended for oral use may contain, for example, one or more coloring,sweetening, flavoring and/or preservative agents.

Suitable pharmaceutically-acceptable excipients for a tablet formulationinclude, for example, inert diluents such as lactose, sodium carbonate,calcium phosphate or calcium carbonate, granulating and disintegratingagents such as corn starch or algenic acid; binding agents such asstarch; lubricating agents such as magnesium stearate, stearic acid ortalc; preservative agents such as ethyl or propyl p-hydroxybenzoate, andanti-oxidants, such as ascorbic acid. Tablet formulations may beuncoated or coated either to modify their disintegration and thesubsequent absorption of the active ingredient within thegastrointestinal tract, or to improve their stability and/or appearance,in either case, using conventional coating agents and procedures wellknown in the art.

Compositions for oral use may be in the form of hard gelatin capsules inwhich the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules in which the active ingredient is mixed with water oran oil such as peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions generally contain the active ingredient in finelypowdered form together with one or more suspending agents, such assodium carboxymethylcellulose, methylcellulose,hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone,gum tragacanth and gum acacia; dispersing or welting agents such aslecithin or condensation products of an alkylene oxide with fatty acids(for example polyoxethylene stearate), or condensation products ofethylene oxide with long chain aliphatic alcohols, for exampleheptadecaethyleneoxycetanol, or condensation products of ethylene oxidewith partial esters derived from fatty acids and a hexitol such aspolyoxyethylene sorbitol monooleate, or condensation products ofethylene oxide with partial esters derived from fatty acids and hexitolanhydrides, for example polyethylene sorbitan monooleate. The aqueoussuspensions may also contain one or more preservatives (such as ethyl orpropyl p-hydroxybenzoate, anti-oxidants (such as ascorbic acid),coloring agents, flavoring agents, and/or sweetening agents (such assucrose, saccharine or aspartame).

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil (such as arachis oil, olive oil, sesame oil orcoconut oil) or in a mineral oil (such as liquid paraffin). The oilysuspensions may also contain a thickening agent such as beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set outabove, and flavoring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water generally contain the activeingredient together with a dispersing or welling agent, suspending agentand one or more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients such as sweetening, flavoring and coloring agents,may also be present.

The pharmaceutical compositions of the invention may also be in the formof oil-in-water emulsions. The oily phase may be a vegetable oil, suchas olive oil or arachis oil, or a mineral oil, such as for exampleliquid paraffin or a mixture of any of these. Suitable emulsifyingagents may be, for example, naturally-occurring gums such as gum acaciaor gum tragacanth, naturally-occurring phosphatides such as soya bean,lecithin, an esters or partial esters derived from fatty acids andhexitol anhydrides (for example sorbitan monooleate) and condensationproducts of the said partial esters with ethylene oxide such aspolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening, flavoring and preservative agents.

Syrups and elixirs may be formulated with sweetening agents such asglycerol propylene glycol, sorbitol, aspartame or sucrose, and may alsocontain a demulcent, preservative, flavoring and/or coloring agent.

The pharmaceutical compositions may also be in the form of a sterileinjectable aqueous or oily suspension, which may be formulated accordingto known procedures using one or more of the appropriate dispersing orwetting agents and suspending agents, which have been mentioned above. Asterile injectable preparation may also be a sterile injectable solutionor suspension in a non-toxic parenterally-acceptable diluent or solvent,for example a solution in 1,3-butanediol.

Suppository formulations may be prepared by mixing the active ingredientwith a suitable non-irritating excipient which is solid at ordinarytemperatures but liquid at the rectal temperature and will thereforemelt in the rectum to release the drug. Suitable excipients include, forexample, cocoa butler and polyethylene glycols.

Topical formulations, such as creams, ointments, gels and aqueous oroily solutions or suspensions; may generally be obtained by formulatingan active ingredient with a conventional, topically acceptable, vehicleor diluent using conventional procedures well known in the art.

Compositions for administration by insufflation may be in the form of afinely divided powder containing particles of average diameter of, forexample, 30 μm or much less, the powder itself comprising either activeingredient alone or diluted with one or more physiologically acceptablecarriers such as lactose. The powder for insufflation is thenconveniently retained in a capsule containing, for example, 1 to 50 mgof active ingredient for use with a turbo-inhaler device, such as isused for insufflation of the known agent sodium cromoglycate.

Compositions for administration by inhalation may be in the form of aconventional pressurized aerosol arranged to dispense the activeingredient either as an aerosol containing finely divided solid orliquid droplets. Conventional aerosol propellants such as volatilefluorinated hydrocarbons or hydrocarbons may be used and the aerosoldevice is conveniently arranged to dispense a metered quantity of activeingredient.

For further information on formulations, see Chapter 25.2 in Volume 5 ofComprehensive Medicinal Chemistry (Corwin Harisch; Chairman of EditorialBoard), Pergamon Press 1990, which is specifically incorporated hereinby reference.

The amount of a compound of this invention that is combined with one ormore excipients to produce a single dosage form will necessarily varydepending upon the subject treated, the severity of the disorder orcondition, the rate of administration, the disposition of the compoundand the discretion of the prescribing physician. However, an effectivedosage is in the range of about 0.001 to about 100 mg per kg body weightper day, preferably about 1 mg/kg/day to about 35 mg/kg/day, in singleor divided doses. For a 70 kg human, this would amount to about 0.07 to2.45 g/day, preferably about 0.05 to about 1.0 g/day. In some instances,dosage levels below the lower limit of the aforesaid range may be morethan adequate, while in other cases still larger doses may be employedwithout causing any harmful side effect, provided that such larger dosesare first divided into several small doses for administration throughoutthe day. For further information on routes of administration and dosageregimes, see Chapter 25.3 in Volume 5 of Comprehensive MedicinalChemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press1990, which is specifically incorporated herein by reference.

The size of the dose for therapeutic or prophylactic purposes of acompound of Formula I-V will naturally vary according to the nature andseverity of the conditions, the age and sex of the animal or patient andthe route of administration, according to well known principles ofmedicine.

The compounds of this invention may be used alone in combination withother drugs and therapies used in the treatment of disease states whichwould benefit from the inhibition of MEK. Such treatment may involve, inaddition to the compounds of the invention, conventional surgery orradiotherapy or chemotherapy. Such chemotherapy may include one or moreof the following categories of anti-tumor agents:

(i) antiproliferative/anti-neoplastic drugs and combinations thereof, asused in medical oncology, such as alkylating agents (for example,cis-platin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan,chlorambucil, busulphan and nitrosoureas); anti-metabolites (forexample, antifolates such as such as fluoropyrimidines like5-fluorouracil and tegafur, raltilrexed, methotrexate, cytosinearabinside, hydroxyurea, or, one of the preferred anti-metabolitesdisclosed in European Patent Application No. 239362 such asN-(5-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-methylamino]-2-thenoyl)-L-glutamicacid): antitumor antibiotics (for example, anthracyclines likeadriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin,mitomycin-C, dactinomycin and mithramycin); antimitotic agents (forexample, vinca alkaloids like vincristine, vinblastine, vindesine andvinorelbine and taxoids like taxol and taxotere); and topoisomeraseinhibitors (for example epipodophyllotoxins like eptoposide andteniposide, amsacrine, topotecan and campothecin):

(ii) cytostatic agents such as antiestrogens (for example, tamoxifen,toremifene, raloxifene, droloxifene and iodoxyfene), estrogen receptordown regulators (for example, fulvestratrant) antiandrogens (forexample, bicalutamide, fiutamide, nilutamide, cyproxerone acetate andCasodex™(4′-cyano-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methyl-3′-(trifluoromethyl)propionanilide)),LHRH antagonists or LHRH agonists (for example, goserelin, leuporelinand buserelin), progestogens (for example, megestrol acetate), aromataseinhibitors (for example, asanastrozole, letrozole, vorazole andexemestane) and inhibitors of 5α-reductase such as finasteride;

(iii) agents which inhibit cancer cell invasion (for example,metalloproteinase inhibitors like marimastat and inhibitors of urokinaseplasminogne activator receptor function);

(iv) inhibitors of growth factor function like growth factor antibodies,growth factor receptor antibodies (for example, the anti-erbB2 antibodytrastumuzab [Herceptin™] and the anti-erbB1 antibody cetuximab [C225]),farnesyl transferase inhibitors, tyrosine kinase inhibitors andserine-threonine kinase inhibitors (for example, inhibitors of theepidermal growth factor family tyrosine kinases such asN-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine(gefitinib, AZD1839),N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine(erlotinib, OSI-774) and6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)quinazolin-4-amine(Cl 1033)), inhibitors of the platelet-derived growth factor family andinhibitors of the hepatocyte growth factor family;

(v) antiangiogenic agents such as those which inhibit the effects ofvascular endothelial growth factor (for example, the anti-vascularendothelial cell growth factor antibody bevacizumab [Avastin™],compounds such as those disclosed in PCT Publication Nos. WO 97/22596,WO 97/30035, WO 97/32856, and WO 98/13354) and compounds that work byother mechanisms (for example, linomide, inhibitors of integrin αvβ3function, MMP inhibitors, COX-2 inhibitors and angiostatin);

(vi) vascular damaging agents such as Combretastatin A4 and compoundsdisclosed in PCT Publication Nos. WO 99/02166, WO 0/40529, WO 00/41669,WO 01/92224, WO 02/04434, and WO 02/08213;

(vii) antisense therapies (for example, those which are directed to thetargets listed above such as ISIS 2503, and anti-ras antisense);

(viii) gene therapy approaches, including for example GVAX™, approachesto replace aberrant genes such as aberrant p53 or aberrant BRCA1 orBRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such asthose using cytosine deaminase, thymidine kinase or a bacterialnitroreductase enzyme and approaches to increase patient tolerance tochemotherapy or radiotherapy such as multi-drug resistance gene therapy:

(ix) interferon; and

(x) immunotherapy approaches, including for example ex-vivo and in-vivoapproaches to increase the immunogenicity of patient tumor cells, suchas transfection with cytokines such as interleukin 2, interleukin 4 orgranulocyte-macrophage colony stimulating factor, approaches to decreaseT-cell anergy, approaches to using transfected immune cells such ascytokine-transfected dendritic cells, approaches usingcytokine-transfected tumor cell lines and approaches usinganti-idiotypic antibodies.

Such conjoint treatment may be achieved by way of the simultaneous,sequential or separate dosing of the individual components of treatment.Such combination products employ the compounds of this invention withinthe dose range described hereinbefore and the other pharmaceuticallyactive agent within its approved dose range.

According to this aspect of the invention there is provided apharmaceutical product comprising a compound of Formula I-V as definedherein and an additional anti-tumor agent as defined hereinbefore forthe conjoint treatment of cancer.

Although the compounds of Formula I-V are primarily of value astherapeutic agents for use in warm-blooded animals (including man), theyare also useful whenever it is required to inhibit the effects of MEK.Thus, they are useful as pharmacological standards for use in thedevelopment of new biological tests and in the search for newpharmacological agents.

The activity of the compounds of the present invention may be determinedby the following procedure. N-terminal 6 His-tagged, constitutivelyactive MEK-1 (2-393) is expressed in E. coli and protein is purified byconventional methods (Ahn et al., Science 1994, 265, 966-970). Theactivity of MEK1 is assessed by measuring the incorporation ofγ-³³P-phosphate from γ-³³P-ATP onto N-terminal His tagged ERK2, which isexpressed in E. coli and is purified by conventional methods, in thepresence of MEK-1. The assay is carried out in 96-well polypropyleneplate. The incubation mixture (100 μL) comprises of 25 mM Hepes, pH 7.4,10 mM MgCb, 5 mM β-glycerolphosphate, 100 μM Na-orthovanadate, 5 mM DTT,5 nM MEK1, and 1 μM ERK2. Inhibitors are suspended in DMSO, and altreactions, including controls are performed at a final concentration of1% DMSO. Reactions are initialed by the addition of 10 μM ATP (with 0.5μCi γ-³³P-ATP/well) and incubated at ambient temperature for 45 minutes.Equal volume of 25% TCA is added to stop the reaction and precipitatethe proteins. Precipitated proteins are trapped onto glass fiber Bfilterplates, and excess labeled ATP washed off using a Tomtec MACH IIIharvestor. Plates are allowed to air-dry prior to adding 30 μL/well ofPackard Microscint 20, and plates are counted using a Packard TopCount.In this assay, compounds of the invention exhibited an IC₅₀ of less than50 micromolar.

Representative compounds of the present invention, which are encompassedby the present invention include, but are not limited to the compoundsof the examples and their pharmaceutically acceptable acid or baseaddition salts or prodrugs thereof. The examples presented below areintended to illustrate particular embodiments of the invention, and arenot intended to limit the scope of the specification or the claims inany way.

The disclosures in this application of all articles and references,including patents, are incorporated herein by reference.

In another embodiment of the invention, an article of manufacture, or“kit”, containing materials useful for the treatment of the disordersdescribed above is provided. In one embodiment, the kit comprises acontainer comprising a compound of Formula I-V or a formulation thereof.The kit may also comprise a label or package insert on or associatedwith the container. The term “package insert” is used to refer toinstructions customarily included in commercial packages of therapeuticproducts, that contain information about the indications, usage, dosage,administration, contraindications and/or warnings concerning the use ofsuch therapeutic products. Suitable containers include, for example,bottles, vials, syringes, blister pack, etc. The container may be formedfrom a variety of materials such as glass or plastic. The containerholds a compound of Formula I-V or a formulation thereof which iseffective for treating the condition and may have a sterile access port(for example, the container may be an intravenous solution bag or a vialhaving a stopper pierceable by a hypodermic injection needle). The labelor package insert may indicate that the composition is used for treatingthe condition of choice, such as cancer. In one embodiment, the label orpackage inserts indicates that the compound of Formula I-V or aformulation thereof can be used to treat a disease or medical conditionmediated by MEK. In addition, the label or package insert may indicatethat the patient to be treated is one having a disease or medicalcondition mediated by MEK such as a hyperproliferative disorder or aninflammatory condition. The label or package insert may also indicatethat the composition can be used to treat other disorders.Alternatively, or additionally, the article of manufacture may furthercomprise a second container comprising a pharmaceutically-acceptablebuffer, such as bacteriostatic water for injection (BWFI),phosphate-buffered saline. Ringer's solution and dextrose solution. Itmay further include other materials desirable from a commercial and userstandpoint, including other buffers, diluents, filters, needles, andsyringes.

According to another embodiment, a kit may comprise (a) a firstcontainer with a compound of Formula I-V or a formulation thereofcontained therein: and optionally (b) a second container with a secondpharmaceutical formulation contained therein, wherein the secondpharmaceutical formulation comprises a second compound withanti-hyperproliferative or anti-inflammatory activity. Alternatively, oradditionally, the article of manufacture may further comprise a thirdcontainer comprising a pharmaceutically-acceptable buffer, such asbacteriostatic water for injection (BWFI), phosphate-buffered saline,Ringer's solution and dextrose solution. It may further include othermaterials desirable from a commercial and user standpoint, includingother buffers, diluents, filters, needles, and syringes.

The kit may further comprise directions for the administration of acompound of Formula I or a formulation thereof and, if present, thesecond pharmaceutical formulation. For example, if the kit comprises acompound of Formula I-V or a formulation thereof (“first formulation”)and a second pharmaceutical formulation, the kit may further comprisedirections for the simultaneous, sequential or separate administrationof the first and second pharmaceutical compositions to a patient in needthereof.

In another embodiment, the kits are suitable for the delivery of solidoral forms of a compound of Formula I-V, such as tablets or capsules.Such a kit preferably includes a number of unit dosages. Such kits caninclude a card having the dosages oriented in the order of theirintended use. An example of such a kit is a “blister pack”. Blisterpacks are well known in the packaging industry and are widely used forpackaging pharmaceutical unit dosage forms. If desired, a memory aid canbe provided; for example in the form of numbers, letters, or othermarkings or with a calendar insert, designating the days in thetreatment schedule in which the dosages can be administered.

In certain other embodiments wherein the kit comprises a compound ofFormula I-V or a formulation thereof and a second therapeutic agent, thekit may comprise a container for containing the separate components suchas a divided bottle or a divided foil packet, however, the separatecompositions may also be contained within a single, undivided container.Typically, the kit comprises directions for the administration of theseparate components. The kit form is particularly advantageous when theseparate components are preferably administered in different dosageforms (e.g., oral and parenteral), are administered at different dosageintervals, or when titration of the individual components of thecombination is desired by the prescribing physician.

EXAMPLES

In order to illustrate the invention, the following examples areincluded. However, it is to be understood that these examples do notlimit the invention and are only meant to suggest a method of practicingthe invention. Persons skilled in the art will recognize that thechemical reactions described may be readily adapted to prepare a numberof other MEK inhibitors of the invention, and alternative methods forpreparing the compounds of this invention are deemed to be within thescope of this invention. For example, the synthesis of non-exemplifiedcompounds according to the invention may be successfully performed bymodifications apparent to those skilled in the art, e.g., byappropriately protecting interfering groups, by utilizing other suitablereagents known in the art other than those described, and/or by makingroutine modifications of reaction conditions. Alternatively, otherreactions disclosed herein or known in the art will be recognized ashaving applicability for preparing other compounds of the invention.

In the examples described below, unless otherwise indicated alttemperatures are set forth in degrees Celsius. Reagents were purchasedfrom commercial suppliers such as Aldrich Chemical Company. Lancaster,TCI or Maybridge, and were used without further purification unlessotherwise indicated. Tetrahydrofuran (THF). N,N-dimethylformamide (DMF),dichloromethane, toluene, dioxane and 1,2-difluoroethane were purchasedfrom Aldrich in Sure seal bottles and used as received.

The reactions set forth below were done generally under a positivepressure of nitrogen or argon or with a drying lube (unless otherwisestated) in anhydrous solvents, and the reaction flasks were typicallyfitted with rubber septa for the introduction of substrates and reagentsvia syringe. Glassware was oven dried and/or heat dried.

Column chromatography was done on a Biotage system (Manufacturer: DyaxCorporation) having a silica gel column or on a silica SepPak cartridge(Waters).

¹H-NMR spectra were recorded on a Varian instrument operating at 400MHz. ¹H-NMR spectra were obtained as CDCl₃ solutions (reported in ppm),using chloroform as the reference standard (7.25 ppm). Other NMRsolvents were used as needed. When peak multiplicities are reported, thefollowing abbreviations are used: s (singlet), d (doublet), t (triplet),m (multiplet), br (broadened), dd (doublet of doublets), dt (doublet oftriplets). Coupling constants, when given, are reported in Hertz (Hz).

Example 1

4-(4-Bromo-2-fluorophenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid

Step A: Preparation of4-hydroxy-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid ethylester: Triethyl orthoformate (45.82 mL, 275.5 mmol) and acetic anhydride(52.08 mL, 550.9 mmol) were added to diethyl acetone dicarboxylate (50mL, 275.5 mmol) and heated to 135° C. After 1 hour, the reaction mixturewas cooled to room temperature and concentrated. The resulting residuewas cooled to 0° C. and methylamine (40% in water) was added withstirring. After the addition of water (200 mL) the reaction mixture wasstirred at room temperature for 16 hours. The reaction mixture wasdiluted with EtOAc (300 mL), and the resulting layers separated. Theaqueous phase was neutralized with 10% HCl solution to produce thedesired product as a white precipitate, which was filtered and washedwith water, five filtrate was extracted with EtOAc, and the combinedorganic extracts dried (MgSO₄), and concentrated to give a white solid.This second crop of product was rinsed with Et₂O and combined with thefirst crop to yield 29 g (54%) desired product after drying.

Step B: Preparation of4-chloro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid ethylester: Triethyl amine (7.07 mL, 50.7 mmol) was added to a suspension of4-hydroxy-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid ethylester (10.0 g, 50.7 mmol) and POCl₃ (27.85 mL, 304.3 mmol). Afterstirring 16 hours, the reaction mixture was concentrated under reducedpressure. The resulting residue was poured onto ice, carefullyneutralized with saturated K₂CO₃ solution, and diluted with EtOAc. Thelayers were separated and the aqueous phase further extracted withEtOAc. The combined organic extracts were dried (MgSO₄) and concentratedunder reduced pressure to yield 7.3 g (67%) clean desired product.

Step C: Preparation of4-chloro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid: To asolution of 4-chloro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid ethyl ester (0.925 g, 4.29 mmol) in a 4:1 mixture of THF:MeOH (20ml) was added a 1 M solution of LiOH (8.6 mL). After stirring for 30minutes, the reaction mixture was acidified to pH 1 with 10% HCl andextracted with EtOAc. The combined organic extracts were washed withbrine, dried (MgSO₄) and concentrated under reduced pressure to give0.732 g (91%) clean desired product.

Step D: Preparation of4-(4-bromo-2-fluorophenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid: To a solution of i-Pr₂NH (0.39 mL, 2.80 mmol) in THF (4 mL) at 0°C. was added n-BuLi (1.1 mL, 2.80 mmol, 2.5 M solution in hexanes).After stirring 15 minutes, the mixture was cooled to −78° C.4-Bromo-2-fluorophenylamine (0.38 g, 2.0 mmol) was added. After vigorousstirring for 10 minutes, a mixture of the4-chloro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid (0.15 g,0.80 mmol) in THF (5 mL) was added. The dry-ice bath was removed after30 minutes, and the reaction mixture was stirred for 17 hours at roomtemperature. The reaction mixture was treated with a 10% aqueous HClsolution (15 mL), extracted with EtOAc, dried (MgSO₄), and concentrated.Trituration with methylene chloride gave 0.21 g (77%) desired product.MS APCI (−) m/z 339, 341 (M−, Br pattern) detected; ¹H NMR (400 mHz,DMSO-d₆) δ 9.61 (s, 1H), 8.53 (s, 1H), 7.69 (dd, 1H), 7.46 (m, 2H), 3.41(s, 3H).

In the foregoing examples a variety of anilines can be used in replaceof 4-bromo-2-fluorophenylamine in Step D of Example 1.

Example 2

4-(4-Bromo-2-fluorophenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid cyclopropylmethoxy-amide

Preparation of4-(4-bromo-2-fluorophenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid cyclopropylmethoxy-amide: A mixture of4-(4-bromo-2-fluorophenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid (0.078 g, 0.229 mmol), EDCl (0.13 g, 0.69 mmol), and HOBt (0.093 g,0.69 mmol) in DMF (5 mL) was stirred for 30 minutes.O-Cyclopropylmethyl-hydroxylamine (0.060 g, 0.69 mmol) was addedfollowed by Et₃N (0.096 mL, 0.69 mmol). After 1 hour, the reactionmixture was diluted with EtOAc and washed with saturated NH₄Cl solution,saturated NaHCO₃ solution and brine. The organic layer was dried (MgSO₄)and concentrated to yield 83 mg (89%) clean desired product. MS APCI (+)m/z 410, 412 (M+, Br pattern) detected; ¹H NMR (400 mHz, DMSO-d₆) δ11.57 (s, 1H), 9.42 (s, 1H), 8.10 (s, 1H), 7.67 (d, 1H), 7.43 (m, 2H),3.70 (d, 2H), 3.35 (s, 3H), 1.11 (m, 1H), 0.54 (m, 2H), 0.27 (m, 2H).

Any of the hydroxylamines used in the foregoing examples can be coupledas described in Example 2. In some instances, a final deprotection stepmay be required. These deprotections can be accomplished by standardliterature methods. Example 3 is one such example in which a finaldeprotection step is required.

Example 3

4-(4-Bromo-2-fluorophenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid (2-hydroxyethoxy)-amide

Step A: Preparation of4-(4-bromo-2-fluorophenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid (2-vinyloxyethoxy)-amide: A mixture or4-(4-bromo-2-fluorophenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid (0.120 g, 0.352 mmol), EDCl (0.10 g, 0.53 mmol), and HOBt (0.071 g,0.53 mmol) in DMF (5 mL) was stirred for 3 hours.O-(2-Vinyloxy-ethyl)-hydroxylamine (0.071 mL, 0.70 mmol) was addedfollowed by Et₃N (0.098 mL, 0.70 mmol). After 2 hours, the reactionmixture was diluted with EtOAc and washed with saturated NH₄Cl solution,saturated NaHC₃ solution and brine. The organic layer was dried (MgSO₄)and concentrated under reduced pressure. Purification by flash columnchromatography (3% MeOH in methylene chloride) gave 0.078 g (52%) cleandesired product.

Step B: Preparation of4-(4-bromo-2-fluorophenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid (2-hydroxyethoxy)-amide: 1 N HCl solution (0.36 mL) was added to astirred solution of4-(4-bromo-2-fluorophenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid (2-vinyloxyethoxy)-amide (0.077 g, 0.181 mmol) in a 1:1 mixture ofEtOH:THF (6 mL). After 1 hour, the pH of the reaction mixture wasadjusted to 5 to 7 with 2 N NaOH solution. The reaction mixture wasdiluted with EtOAc, washed with water, dried (MgSO₄) and concentrated.Trituration with diethyl ether yielded 55 mg (76%) clean desired productas a white solid. MS APCI (−) m/z 398, 400 (M−, Br pattern) detected: ¹HNMR (400 mHz, DMSO-d₆)<11.65 (s, 1H), 9.41 (s, 1H), 8.13 (s, 1H), 7.68(d, 1H), 7.43 (m, 3H), 4.74 (t, 1H), 3.91 (t, 2H), 3.62 (m, 2H), 3.36(s, 3H).

Example 4

4-(4-Bromo-2-fluorophenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid amide

Preparation of4-(4-bromo-2-fluorophenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid amide: A mixture of4-(4-bromo-2-fluorophenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid (0.069 g, 0.202 mmol), EDCl (0.1.2 g, 0.61 mmol), and HOBt (0.082g, 0.61 mmol) in DMF (5 mL) was stirred for 30 minutes. NH₄Cl (0.033 g,0.61 mmol) was added followed by Et₃N (0.085 mL, 0.61 mmol). After 1hour, the reaction mixture was diluted with EtOAc and washed withsaturated NH₄Cl solution, saturated NaHCO₃ solution and brine. Theorganic layer was dried (MgSO₄) and concentrated to yield 52 mg (76%)clean desired product as an off-white solid. MS APCI (+) m/z 340, 342(M+, Br pattern) detected: ¹H NMR (400 mHz, DMSO-d₆) 10.39 (s, 1H), 8.34(s, 1H), 7.67 Odd, 1H), 7.43 (m, 2H), 3.36 (s, 3H).

The following compounds were prepared as described in Examples 1, 2 and3 using benzyl amine in place of methylamine in Step A of Example 1 andno Et₃N in Step B of Example 1.

Example 5

1-Benzyl-4-(4-bromo-2-fluorophenylamino)-6-oxo-1,6-dihydropyridine-3-carboxylicacid

MS APCI (−) m/z 415, 417 (M−, Br pattern) detected; ¹H NMR (400 mHz,DMSO-d₆) 9.62 (s, 1H), 8.60 (s, 1H), 7.65 (dd, 1H), 7.48 (m, 2H), 7.32(m, 5H), 5.49 (s, 1H), 5.12 (s, 2H).

Example 6

1-Benzyl-4-(4-bromo-2-fluorophenylamino)-6-oxo-1,6-dihydropyridine-3-carboxylicacid cyclopropylmethoxy amide

MS APCI (−) m/z 484, 486 (M−, Br pattern) detected; ¹H NMR (400 mHz,CD₃OD) δ 8.04 (s, 1H), 7.49 (d, 1H), 7.40 (m, 2H), 7.32 (m, 6H), 5.12(s, 2H), 3.75 (d, 2H), 1.14 (m, 1H), 0.57 (m, 2H), 0.28 (m, 2H).

Example 7

1-Benzyl-4-(4-bromo-2-fluorophenylamino)-6-oxo-1,6-dihydropyridine-3-carboxylicacid (2-hydroxyethoxy) amide

MS APCI (−) m/z 474, 476 (M−, Br pattern) detected; ¹H NMR (400 mHz,CD₃OD) δ 8.10 (s, 1H), 7.49 (d, 1H), 7.40 (m, 2H), 7.33 (m, 6H), 5.12(s, 2H), 4.03 (t, 2H), 3.77 (t, 2H).

The following compounds were prepared as previously described with theaddition of a chlorination step. An example of such a chlorination isdescribed below.

A mixture of 4-chloro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid ethyl ester (1.00 g, 4.64 mmol) and NCS (0.68 g, 5.10 mmol) in DMF(30 mL) was stirred for 1 hour. The reaction mixture was diluted withEtOAc and washed with 0.1 N HCl solution. The organic layer was dried(MgSO₄) and concentrated under reduced pressure to give 1.10 g (95%) of4,5-dichloro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid ethylester.

Example 8

4-(4-Bromo-2-fluorophenylamino)-5-chloro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid cyclopropylmethoxy amide

MS APCI (+) m/z 444, 446 (M+, Cl, Br pattern) detected; ¹H NMR (400 mHz,DMSO-d₆) δ 11.52 (s, 1H), 8.78 (s, 1H), 7.98 (s, 1H), 7.52 (dd, 1H),7.29 (dd, 1H), 6.93 (t, 111), 3.47 (s, 3H), 3.40 (d, 2H), 1.01 (m, 1H),0.50 (m, 2H), 0.20 (m, 2H).

Example 9

4-(4-Bromo-2-fluorophenylamino)-5-chloro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid amide

MS APCI (+) m/z 374, 376 (M+, Cl, Br pattern) detected; ¹H NMR (400 mHz,DMSO-d₆) δ 10.16 (s, 1H), 8.33 (s, 1H), 7.99 (br. s, 1H), 7.64 (br, s,1H), 7.55 (dd, 1H), 7.30 (dd, 1H), 6.90 (m, 1H), 3.48 (s, 3H).

Example 10

4-(4-Bromo-2-fluorophenylamino)-5-chloro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid (2-hydroxyethoxy)-amide

MS APCI (+) m/z 434, 436 (M+, Cl, Br pattern) detected; ¹H NMR (400 mHz,DMSO-d₆) δ 11.60 (s, 1H), 8.82 (s, 1H), 8.03 (s, 1H), 7.52 (dd, 1H),7.28 (d, 1H), 6.92 (t, 1H), 4.69 (t, 1H), 3.68 (m, 2H), 3.52 (m, 2H),3.47 (s, 3H).

Example 11

4-<4-Bromo-2-fluorophenylamino)-5-chloro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid

MS APCI (+) m/z 375, 377 (M+, Cl, Br pattern) detected; ¹H NMR (400 mHz,DMSO) 59.58 (s, 1H), 8.58 (s, 1H), 7.57 (dd, 1H), 7.33 (d, 1H), 7.0 (t,1H), 3.53 (s, 3H).

Example 12

4-(4-Bromo-2-fluorophenylamino)-5-chloro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid ethoxy-amide

MS APCI (+) m/z 418, 420 (M+, Cl, Br pattern) detected; ¹H NMR (400 mHz,CD₃OD) δ 7.85 (s, 1H), 7.34 (dd, 1H), 7.26 (dd, 1H), 6.97 (t, 1H), 3.69(q, 2H), 3.58 (s, 3H), 1.20 (t, 3H).

Example 13

1-Benzyl-4-(4-bromo-2-fluorophenylamino)-5-chloro-6-oxo-1,6-dihydropyridine-3-carboxylicacid

MS APCI (−) m/z 449, 451 (M−, Cl, Br pattern) detected; ¹H NMR (400 mHz,DMSO-d₆) 9.66 (s, 1H), 8.67 (s, 1H), 7.56 (d, 1H), 7.34 (m, 6H), 7.03(t, 1H), 5.23 (s, 2H).

Example 14

1-Benzyl-4-(4-bromo-2-fluorophenylamino)-5-chloro-6-oxo-1,6-dihydropyridine-3-carboxylicacid amide

MS APCI (−) m/z 448, 450 (M−, Cl, Br pattern) detected; ¹H NMR (400 mHz,DMSO-D₆) δ 10.21 (s, 1H), 8.45 (s, 1H), 8.07 (br. s, 1H), 7.65 (br. s,1H), 7.53 (dd, 1H), 7.33 (m, 6H), 6.94 (t, 1H), 5.12 (s, 2H).

Example 15

1-Benzyl-4-(4-bromo-2-fluorophenylamino)-5-chloro-6-oxo-1,6-dihydropyridine-3-carboxylicacid cyclopropylmethoxy-amide

MS APCI (−) m/z 518, 520 (M−, Cl, Br pattern) detected; ¹H NMR (400 mHz,DMSO-d₆) δ 8076 (s, 1H), 8.08 (s, 1H), 7.51 (d, 1H), 7.35 (m, 6H), 6.96(t, 1H), 5.11 (s, 2H), 3.36 (d, 2H), 0.99 (m, 1H), 0.49 (m, 2H), 0.19(m, 2H).

Example 16

1-Benzyl-4-(4-bromo-2-fluorophenylamino)-5-chloro-6-oxo-1,6-dihydropyridine-3-carboxylicacid (2-hydroxyethoxy)-amide

MS APCI (−) m/z 508, 510 (M−, Cl, Br pattern) detected: ¹H NMR (400 mHz,DMSO-d₆) 8.80 (s, 1H), 8.13 (s, 1H), 7.51 (dd, 1H), 7.35 (m, 6H), 7.27(d, 1H), 6.95 (t, 1H), 5.12 (s, 2H), 4.67 (t, 1H), 3.65 (m, 2H), 3.51(m, 2H).

The following compounds were prepared as previously described with theaddition of a fluorination step. An example of such a fluorination isdescribed below.

A mixture of 4-chloro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid ethyl ester (1.00 g, 4.64 mmol), LiOH (0.22 g, 9.30 mmol) and[1-(chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane-bis(tetrafluoroborate)(3.30 g, 9.30 mmol) in MeCN (50 mL) was stirred al 85° C. for 1 hour.The reaction was cooled to room temperature and concentrated underreduced pressure. The residue was dissolved in water and extracted withEtOAc. The combined organic extracts were dried (MgSO₄) and concentratedunder reduced pressure. Flash column chromatography (60:40hexanes:EtOAc) removed starting material. The partially purified ethylester was then hydrolyzed by dissolving in 4:1 THF:MeOH (10 mL) followedby treatment with 1 M LiOH solution (2.8 mL). After 1 hour, the reactionmixture was acidified to pH 1 with 10% HCl solution and extracted withEtOAc. The combined organic extracts were washed with brine, dried(MgSO4) and concentrated to yield 0.25 g (26% for two steps)4-chloro-5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid,which could be further purified by trituration with diethyl ether.

Example 17

4-(4-Bromo-2-fluorophenylamino)-5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid cyclopropylmethoxy-amide

MS APCI (+) m/z 428, 430 (M+, Br pattern) detected: ¹H NMR (400 mHz,CD₃OD) δ 7.85 (s, 1H), 7.36 (dd, 1H), 7.28 (d, 1H), 7.01 (m, 1H), 3.69(d, 2H), 3.57 (s, 3H), 0.89 (m, 1H), 0.58 (m, 2H), 0.30 (m, 2H).

Example 18

4-(4-Bromo-2-fluorophenylamino)-5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid (2-hydroxyethoxy)-amide

MS APCI (+) m/z 418, 420 (M+, Br pattern) detected; ¹H NMR (400 mHz.CD₃OD) δ 7.90 (s, 1H), 7.36 (dd, 1H), 7.28 (dd, 111), 7.01 (m, 1H), 3.98(m, 2H), 3.75 (m, 2H), 3.58 (s, 3H).

Example 19

4-(4-Bromo-2-fluorophenylamino)-5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid

MS APCI (−) m/z 357, 359 (M−1, Br pattern) detected; ¹H NMR (400 mHz.CD₃OD) δ 8.33 (s, 1H), 7.30 (d, 1H), 7.26 (d, 1H), 7.03 (td, 1H), 3.62(s, 3H).

Example 20

4-(4-Bromo-2-fluorophenylamino)-5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid amide

MS (+) m/z 358, 360 (M+, Br pattern) detected: ¹H NMR (400 mHz. CD₃OD) δ8.11 (s, 1H), 7.36 (dd, 1H), 7.28 (dd, 1H), 7.02 (m, 1H), 3.58 (s, 3H).

Example 21

4-(4-Bromo-2-fluorophenylamino)-5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid ethoxy-amide

MS APCI (+) m/z 402, 404 (M+, Br pattern) detected; ¹H NMR (400 mHz,CD₃OD) δ 7.87 (s, 1H), 7.35 (dd, 1H), 7.27 (d, 1H), 7.01 (td, 1H), 3.94(q, 2H), 3.58 (s, 3H), 1.27 (t, 3H).

Example 22

4-(4-Bromo-2-fluorophenylamino)-5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid methoxy-amide

MS APCI (+) m/z 388, 390 (M+, Br pattern) detected; ¹H NMR (400 mHz,CD₃OD) δ 7.87 (s, 1H), 7.35 (dd, 1H), 7.27 (d, 1H), 7.01 (td, 1H), 3.75(s, 3H), 3.58 (s, 3H).

Example 23

4-(4-Chloro-2-fluorophenylamino)-5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid cyclopropylmethoxy-amide

MS APCI (+) m/z 384, 386 (M+, Cl pattern) detected; ¹H NMR (400 mHz.CD₃OD) δ 7.56 (s, 1H), 6.93 (dd, 1H), 6.85 (d, 1H), 6.79 (Id, 1H), 3.41(d, 2H), 3.28 (s, 3H), 0.87 (m, 1H), 0.29 (q, 2H), 0.01 (q, 2H).

Example 24

4-(4-Chloro-2-fluorophenylamino)-5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid ethoxy-amide

MS APCI (+) m/z 358, 360 (M+, Cl pattern) detected: ¹H NMR (400 mHz,CD₃OD) δ 7.88 (s, 1H), 7.22 (d, 1H), 7.14 (d, 1H), 7.08 (td, 1H), 3.95(q, 2H), 3.58 (s, 3H), 1.28 (t, 3H).

Example 25

4-(4-Chloro-2-fluorophenylamino)-5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid amide

MS APCI (+) m/z 314, 316 (M+, Cl pattern) detected; ¹H NMR (400 mHz,DMSO) δ 9.96 (s, 1H), 8.23 (s, 1H), 7.99 (bs, 1H), 7.64 (bs, 1H), 7.45(dd, 1H), 7.21 (d, 1H), 7.09 (td, 1H), 3.46 (s, 3H).

Example 26

5-Fluoro-4-(2-fluoro-4-methylphenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid cyclopropylmethoxy-amide

MS APCI (+) m/z 364 (M+1) detected: H NMR (400 mHz. CD₃OD) δ 7.82 (s,1H), 7.0 (td, 1H), 6.94 (d, 1H), 6.93 (s, 1H), 3.69 (d, 2H), 3.56 (s,3H), 2.32 (s, 3H), 1.16 (m, 1H), 0.58 (q, 2H), 0.30 (q, 2H).

Example 27

5-Fluoro-4-(2-fluoro-4-methylphenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid ethoxy-amide

MS APCI (+) m/z 338 (M+1) detected; ¹H NMR (400 mHz, CD₃OD) δ 7.85 (s,1H), 7.0 (td, 1H), 6.94 (d, 1H), 6.93 (s, 1H), 3.93 (q, 2H), 3.56 (s,3H), 2.32 (s, 3H), 1.27 (t, 3H).

Example 28

4-(4-Bromo-2-methylphenylamino)-5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid ethoxy-amide

MS APCI (+) m/z 398, 400 (M+, Br pattern) detected; ¹H NMR (400 mHz,CD₃OD) δ 7.84 (s, 1H), 7.35 (s, 1H), 7.25 (dd, 1H), 6.85 (dd, 1H), 3.92(q, 2H), 3.57 (s, 3H), 2.30 (s, 3H), 1.28 (t, 3H).

Example 29

4(4-Bromo-2-methylphenylamino)-5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid cyclopropylmethoxy-amide

MS APCI (+) m/z 424, 426 (M+, Br pattern) detected; ¹H NMR (400 mHz,CD₃OD) δ 7.82 (s, 1H), 7.35 (s, 1H), 7.25 (dd, 1H), 6.85 (dd, 1H), 3.67(d, 2H), 3.57 (s, 3H), 2.29 (s, 3H), 1.16 (m, 1H), 0.59 (q, 2H), 0.31(q, 2H).

Example 30

4-(4-Bromo-2-fluorophenylamino)-5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid tert-butoxy-amide

MS APCI (+) m/z 430, 432 (M+, Br pattern) detected; ¹H NMR (400 mHz,CD₃OD) δ 7.94 (s, 1H), 7.36 (dd, 1H), 7.28 (d, 1H), 7.01 (td, 1H), 3.60(s, 3H), 1.30 (s, 9H).

Example 31

4-(4-Bromo-2-fluorophenylamino)-5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid cyclopropylmethyl-amide

MS APCI (+) m/z 412, 414 (M+, Br pattern) detected: ¹H NMR (400 mHz,CD₃OD) δ 7.97 (s, 1H), 7.32 (dd, 1H), 7.25 (d, 1H), 6.98 (td, 1H), 3.60(s, 3H), 3.15 (d, 2H), 1.04 (m, 1H), 0.54 (q, 2H), 0.26 (q, 2H).

Example 32

4-(4-Bromo-2-fluorophenylamino)-5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid methylamide

MS APCI (+) m/z 372, 374 (M+, Br pattern) detected; ¹H NMR (400 mHz.CD₃OD) δ 7.93 (s, 1H), 7.35 (dd, 1H), 7.27 (d, 1H), 7.0 (td, 1H), 3.57(s, 3H), 2.83 (s, 3H).

Example 33

5-Fluoro-4-(2-fluoro-4-methylsulfanyl-phenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid ethoxy-amide

Prepared as described previously using2-fluoro-4-methylsulfanyl-phenylamine, which was prepared according toWO 03/062191.

MS APCI (+) m/z 370 μM+1) detected; ¹H NMR (400 mHz, CD₃OD) δ 7.83 (s,1H), 7.03 (m, 3H), 3.96 (q, 2H), 3.58 (s, 3H), 2.48 (s, 3H), 1.29 (t,3H).

Example 34

5-Fluoro-4-(2-fluoro-4-methylsulfanyl-phenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid methoxy-amide,

MS APCI (+) m/z 370 (M+1) detected; ¹H NMR (400 mHz; CD₃OD) δ 7.83 (s,1H), 7.03 (m, 3H), 3.96 (q, 2H), 3.58 (s, 3H), 2.48 (s, 3H), 1.29 (t,3H).

Example 35

5-Fluoro-4-(2-fluoro-4-iodophenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid ethoxy-amide

MS APCI (+) m/z 450 (M+1) detected; ¹H NMR (400 mHz, CD₃OD) δ 7.86 (s,1H), 7.48 (dd, 1H), 7.44 (d, 1H), 6.84 (td, 1H), 3.95 (q, 2H), 3.58 (s,3H), 1.28 (t, 3H).

Example 36

5-Fluoro-4-(2-fluoro-4-iodophenylamino)-1-methyl-6-oxo-1,6-dihydropyridne-3-carboxylicacid methoxy-amide

MS APCI (+) m/z 436 (M+1) detected; ¹H NMR (400 mHz, CD₃OD) δ 7.84 (s,1H), 7.47 (dd, 1H), 7.44 (d, 1H), 6.83 (id, 1H), 3.77 (s, 3H), 3.59 (s,3H).

Example 37

4-(4-Bromo-2-fluorophenylamino)-5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid hydroxyamide

4-(4-Bromo-2-fluorophenylamino)-5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid hydroxyamide was prepared from4-(4-bromo-2-fluorophenylamino)-5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid tert-butoxy-amide by TFA mediated deprotection.4-(4-Bromo-2-fluorophenylamino)-5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid tert-butoxy-amide (35 mg, 0.081 mmol) was treated with TFA (0.63mL). After 4 days stirring, the reaction mixture was concentrated underreduced pressure. Purification by flash column chromatography (10% MeOHin methylene chloride) followed by saturated NaHCO₃ solution wash of anethyl acetate solution of the product gave clean desired product (10 mg,33%); MS APCI (+) m/z 356, 358 (M-OH, Br pattern) detected; ¹H NMR (400mHz. CD₃OD) δ 7.84 (s, 1H), 7.35 (dd, 1H), 7.28 (d, 1H), 7.01 (td, 1H),3.57 (s, 3H).

Example 38

4-(4-Bromo-2-fluorophenylamino)-1-cyclopropylmethyl-5-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid

MS APCI (−) m/z 393, 395 (M−, Br pattern) detected; ¹H NMR (400 MHz,DMSO-d₆) δ 9.12 (s, 1H), 8.51 (s, 1H), 7.56 (d, 1H), 7.28 (d, 1H), 6.69(t, 1H), 3.84 (d, 2H), 1.61 (s, 3H), 1.25 (m, 1H), 0.50 (q, 2H), 0.39(q, 2H).

Example 39

4-(4-Bromo-2-fluorophenylamino)-1-cyclopropylmethyl-5-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid amide

MS APCI (−) m/z 392, 394 (M−, Br pattern) detected; ¹H NMR (400 MHz,CD₃OD) δ 8.14 (s, 1H), 7.33 (d, 1H), 7.21 (d, 1H), 6.63 (t, 1H), 3.87(d, 2H), 1.76 (s, 3H), 1.35 (m, 1H), 0.60 (q, 2H), 0.46 (q, 2H).

Example 40

4-(4-Bromo-2-fluorophenylamino)-1-cyclopropylmethyl-5-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid (2-hydroxy-1,1-dimethylethoxy)-amide

MS APCI (−) m/z 480, 482 (M−, Br pattern) detected; ¹H NMR (400 MHz.DMSO-d₆) δ 11.06 (s, 1H), 8.36 (s, 1H), 8.02 (s, 1H), 7.50 (d, 1H), 7.22(d, 1H), 6.57 (t, 1H), 4.60 (t, 1H), 3.78 (d, 2H), 3.16 (m, 2H), 1.71(s, 3H), 1.29 (m, 1H), 1.11 (s, 6H), 0.51 (q, 2H), 0.43 (q, 2H).

Example 41

(S)-4-(4-Bromo-2-fluorophenylamino)-1-cyclopropylmethyl-5-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid (2-hydroxy-propoxy)-amide

MS APCI (−) m/z 466, 468 (M−, Br pattern) detected; ¹H NMR (400 MHz.CD₃OD) δ 7.93 (s, 1H), 7.34 (dd, 1H), 7.20 (d, 1H), 6.66 (t, 1H), 3.88(m, 1H), 3.86 (d, 2H), 3.71 (dd, 1H), 3.59 (dd, 1H), 1.86 (s, 3H), 1.33(m, 1H), 1.12 (d, 3H), 0.91 (q, 2H), 0.46 (q, 2H).

Example 42

4-<4-Bromo-2-chlorophenylamino)-5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid

MS APCI (−) m/z 373, 375 (M−, Cl, Br pattern) detected; ¹H NMR (4(M)mHz, CD₃OD) δ 8.43 (s, 1H), 7.62 (s, 1H), 7.42 (dd, 1H), 7.01 (m, 1H),3.61 (s, 3H).

Example 43

4-(4-Bromo-2-chlorophenylamino)-5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid cyclopropylmethoxy-amide

MS APCI (+) m/z 444, 446 (M+, Cl, Br pattern) detected; ¹H NMR (400 mHz,CD₃OD) δ 7.89 (s, 1H), 7.60 (d, 1H), 7.39 (dd, 1H), 6.92 (dd, 1H), 3.73(d, 2H), 3.59 (s, 3H), 1.17 (m, 1H), 0.58 (m, 2H), 0.30 (m, 2H).

Example 44

4-<4-Bromo-2-chlorophenylamino)-5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid amide

MS APCI (+) m/z 374, 376 (M+, Cl, Br pattern) detected; ¹H NMR (400 mHz,CD₃OD) δ 8.13 (s, 1H), 7.59 (d, 1H), 7.39 (dd, 1H), 6.92 (dd, 1H), 3.60(s, 3H).

Example 45

4-(4-Bromo-2-chlorophenylamino)-5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid (2-hydroxyethoxy)-amide

MS APCI (+) m/z 434, 436 (M+, Cl, Br pattern) detected; ¹H NMR (400 mHz,CD₃OD) δ 7.94 (s, 1H), 7.60 (d, 1H), 7.40 (dd, 1H), 6.92 (dd, 1H), 4.01(m, 2H), 3.76 (m, 2H), 3.59 (s, 3H).

Example 46

4-(4-Bromo-2-fluorophenylamino-5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid (2-hydroxy-1,1-dimethylethoxy)-amide

MS APCI (+) m/z 446, 448 (M+, Br pattern) detected; ¹H NMR (400 mHz,CD₃OD) δ 7.94 (s, 1H), 7.36 (d, 1H), 7.28 (d, 1H), 7.02 (td, 1H), 3.59(s, 3H), 3.41 (s, 2H), 127 (s, 6H).

Example 47

(S)-4-(4-Bromo-2-fluorophenylamino)-5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid (2-hydroxy-propoxy)-amide

MS APCI (+) m/z 432, 434 (M+, Br pattern) detected; ¹H NMR (400 mHz,CD₃OD) δ 7.89 (s, 1H), 7.36 (d, 1H), 7.28 (d, 1H), 7.02 (td, 1H), 3.99(m, 1H), 3.83 (dd, 1H), 3.72 (dd, 1H), 3.58 (s, 3H), 1.16 (d, 3H).

The following compounds were prepared as previously described by usingthe appropriate amine in place of methylamine in Step A of Example 1.

Example 48

4-(4-Bromo-2-fluorophenylamino)-1-cyclopropyl-5-fluoro-6-oxo-1,6-dihydropyridine-3-carboxylicacid

MS APCI (+) m/z 385, 387 (M+, Br pattern) detected; ¹H NMR (400 mHz,DMSO-D₆) δ 9.29 (s, 1H), 8.08 (s, 1H), 7.58 (dd, 1H), 7.36 (d, 1H), 7.12(m, 1H), 3.35 (m, 1H), 1.02 (m, 2H), 0.90 (m, 2H).

Example 49

4-(4-Bromo-2-fluorophenylamino)-1-cyclopropyl-5-fluoro-6-oxo-1,6-dihydropyridine-3-carboxylicacid cyclopropylmethoxy-amide

MS APCI (+) m/z 454, 456 (M+, Br pattern) detected; ¹H NMR (400 mHz,DMSO-D₆) δ 11.78 (s, 1H), 9.07 (s, 1H), 7.70 (s, 1H), 7.55 (dd, 1H),7.32 (dd, 1H), 7.03 (m, 1H), 3.66 (d, 2H), 3.35 (m, 1H), 1.07 (m, 1H),0.98 (m, 4H), 0.53 (m, 2H), 0.25 (m, 2H).

Example 50

4-(4-Bromo-2-fluorophenylamino)-1-cyclopropyl-5-fluoro-6-oxo-1,6-dihydropyridine-3-carboxylicacid amide

MS APCI (+) m/z 384, 386 (M+, Br pattern) detected; ¹H NMR (400 mHz,DMSO-D₆) δ 10.03 (s, 1H), 8.24 (br, s, 1H), 7.95 (s, 1H), 7.63 (br. s,1H), 7.56 (dd, 1H), 7.33 (d, 1H), 7.00 (m, 1H), 3.35 (m, 1H), 0.99 (m,4H).

Example 51

4-(4-Bromo-2-fluorophenylamino)-1-cyclopropyl-5-fluoro-6-oxo-1,6-dihydropyridine-3-carboxylicacid (2-hydroxyethoxy)-amide

MS APCI (+) m/z 444, 446 (M+, Br pattern) detected; ¹H NMR (400 mHz.DMSO-D₆) δ 11.87 (s, 1H), 9.09 (s, 1H), 7.74 (s, 1H), 7.56 (dd, 1H),7.32 (d, 1H), 7.02 (m, 1H), 3.89 (m, 2H), 3.59 (m, 2H), 3.38 (m, 1H),0.99 (m, 4H).

Example 52

4-(4-Bromo-2-fluorophenylamino)-1-ethyl-5-fluoro-6-oxo-1,6-dihydropyridine-3-carboxylicacid cyclopropylmethoxy-amide

MS APCI (+) m/z 442, 444 (M+, Br pattern) detected; ¹H NMR (400 mHz.CD₃OD) δ 7.85 (s, 1H), 7.36 (dd, 1H), 7.28 (d, 1H), 7.02 (td, 1H), 4.05(q, 2H), 3.70 (d, 2H), 1.36 (t, 3H), 1.17 (m, 1H), 0.58 (q, 2H), 0.31(q, 2H).

Example 53

4-(4-Bromo-2-fluorophenylamino)-1-ethyl-5-fluoro-6-oxo-1,6-dihydropyridine-3-carboxylicacid amide

MS APCI (+) m/z 372, 374 (M+, Br pattern) detected; ¹H NMR (400 mHz,CD₃OD) δ 8.10 (s, 1H), 7.35 (dd, 1H), 7.28 (d, 1H), 7.02 (td, 1H), 4.05(q, 2H), 1.37 (t, 3H).

Example 54

4-(4-Bromo-2-fluorophenylamino)-1-ethyl-5-fluoro-6-oxo-1,6-dihydropyridine-3-carboxylicacid (2-hydroxy-1,1-dimethylethoxy)-amide

MS APCI (+) m/z 460, 462 (M+, Br pattern) detected; ¹H NMR (400 mHz,DMSO) δ 11.20 (bs, 1H), 8.80 (bs, 1H), 8.01 (s, 1H), 7.55 (d, 1H), 7.32(d, 1H), 7.03 (td, 1H), 4.40 (q, 2H), 3.28 (s, 2H), 1.27 (t, 3H), 1.17(s, 6H).

Example 55

4-(4-Bromo-2-fluorophenylamino)-1-ethyl-5-fluoro-6-oxo-1,6-dihydropyridine-3-carboxylicacid (2-methoxy-ethoxy)-amide

MS APCI (+) m/z 446, 448 (M+, Br pattern) detected; ¹H NMR (400 mHz,CD₃OD) δ 7.88 (s, 1H), 7.36 (dd, 1H), 7.28 (d, 1H), 7.02 (td, 1H), 4.05(m, 4H), 3.64 (m, 2H), 3.37 (s, 3H), 1.37 (t, 3H).

Example 56

4-(4-Bromo-2-fluorophenylamino)-1-ethyl-5-fluoro-6-oxo-1,6-dihydropyridine-3-carboxylicacid methoxy-amide

MS APCI (+) m/z 402, 404 (M+, Br pattern) detected; ¹H NMR (400 mHz,CD₃OD) δ 7.87 (s, 1H), 7.36 (d, 1H), 7.29 (d, 1H), 7.02 (td, 1H), 4.02(q, 2H), 3.75 (s, 3H), 1.36 (t, 3H).

Example 57

4-(4-Bromo-2-fluorophenylamino)-1-ethyl-5-fluoro-6-oxo-1,6-dihydropyridine-3-carboxylicacid methylamide

MS APCI (+) m/z 386, 388 (M+, Br pattern) detected; ¹H NMR (400 mHz,CD₃OD) δ 7.93 (s, 1H), 7.35 (dd, 1H), 7.27 (d, 1H), 7.0 (td, 1H), 4.04(q, 2H), 2.83 (s, 3H), 1.37 (t, 3H).

Example 58

4-(4-Bromo-2-fluorophenylamino)-1-ethyl-5-fluoro-6-oxo-1,6-dihydropyridine-3-carboxylicacid

MS APCI (−) m/z 371, 373 (M−, Br pattern) detected; ¹H NMR (400 mHz,CD₃OD) δ 8.41 (s, 1H), 7.38 (d, 1H), 7.30 (d, 1H), 7.10 (td, 1H), 4.08(q, 2H), 1.36 (t, 3H).

Example 59

4-(4-Bromo-2-fluorophenylamino)-1-ethyl-5-fluoro-6-oxo-1,6-dihydropyridine-3-carboxylicacid (2-hydroxyethoxy)-amide

MS APCI (+) m/z 432, 434 (M+, Br pattern) detected; ¹H NMR (400 mHz,CD₃OD) 7.90 (s, 1H), 7.36 (dd, 1H), 7.28 (d, 1H), 7.02 (td, 1H), 4.05(q, 2H), 3.99 (t, 2H), 3.75 (t, 2H), 1.37 (t, 3H).

Example 60

(R)-4-(4-Bromo-2-fluorophenylamino)-1-ethyl-5-fluoro-6-oxo-1,6-dihydropyridine-3-carboxylicacid (2-hydroxy-propoxy)-amide

MS APCI (+) m/z 446, 448 (M+, Br pattern) detected; ¹H NMR (400 mHz,CD₃OD) δ 7.90 (s, 1H), 7.36 (dd, 1H), 7.28 (d, 1H), 7.02 (td, 1H), 4.05(q, 2H), 3.99 (m, 1H), 3.83 (dd, 1H), 3.73 (dd, 1H), 1.36 (t, 3H), 1.16(d, 3H).

Example 61

(S)-4-(4-Bromo-2-fluorophenylamino)-1-ethyl-5-fluoro-6-oxo-1,6-dihydropyridine-3-carboxylicacid (2-hydroxy-propoxy)-amide

MS APCI (+) m/z 446, 448 (M+, Br pattern) detected; ¹H NMR (400 mHz,CD₃OD) δ 7.90 (s, 1H), 7.36 (d, 1H), 7.28 (d, 1H), 7.02 (td, 1H), 4.04(q, 2H), 3.99 (m, 1H), 3.83 (dd, 1H), 3.72 (dd, 1H), 1.36 (t, 3H), 1.16(d, 3H).

Example 62

4-(4-Bromo-2-fluorophenylamino)-1-ethyl-5-fluoro-6-oxo-1,6-dihydropyridine-3-carboxylicacid (2-hydroxybutoxy)-amide

MS APCI (+) m/z 460, 462 μM+, Br pattern) detected; ¹H NMR (400 mHz.CD₃OD) δ 7.90 (s, 1H), 7.36 (dd, 1H), 7.28 (d, 1H), 7.02 (td, 1H), 4.05(q, 2H), 3.89 (d, 1H), 3.75 (m, 2H), 1.54 (m, 1H), 1.45 (m, 1H), 1.36(1, 3H), 0.98 (t, 3H).

Example 63

4-(4-Bromo-2-fluorophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid

Preparation of4-hydroxy-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid ethylester: Triethyl orthoformate (3.85 mL, 23.12 mmol) and acetic anhydride(4.37 mL, 46.25 mmol) were added to 2-methyl-3-oxo-pentanedioic aciddiethyl ester (Caliskan et al Aust. J. Chem. 1999, 52 (11), 1013-1020)(5.0 g, 23.1 mmol) and the reaction mixture heated to 135° C. After 1hour, the reaction mixture was cooled to room temperature andconcentrated under reduced pressure. The residue was cooled to 0° C. andmethylamine (40% in water, 5.0 mL, 57.81 mmol) was added with stirring.Water (20 mL) was added and the reaction mixture stirred for 16 hours.The reaction mixture was extracted with ethyl acetate and the aqueouslayer acidified to pH 2 with 10% aqueous HCl. The acidified aqueouslayer was extracted with ethyl acetate. The combined organic extractswere dried (MgSO₄) and concentrated to give a solid. Trituration withdiethyl ether yielded 4.88 g (55%) clean desired product.4-Hydroxy-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid ethylester was carried forward as described in Example 1, Steps B-D. MS APCI(−) m/z 353, 355 (M−, Br pattern) detected; ¹H NMR (400 mHz, CD₃OD) δ8.49 (s, 1H), 7.36 (dd, 1H), 7.24 (dd, 1H), 6.71 (m, 1H), 3.60 (s, 3H),1.68 (s, 3H).

The following compounds were prepared as described in Examples 1 (StepsB-D), 2, 3 and 63.

Example 64

4-(4-Bromo-2-fluorophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid cyclopropylmethoxy-amide

MS APCI (+) m/z 424, 426 (M+, Br pattern) detected; ¹H NMR (400 mHz,CD₃OD) δ 7.88 (s, 1H), 7.33 (dd, 1H), 7.20 (dd, 1H), 6.65 (m, 1H), 3.59(d, 2H), 3.57 (s, 3H), 1.83 (s, 3H), 1.10 (m, 1H), 0.54 (m, 2H), 0.25(m, 2H).

Example 65

4-(4-Bromo-2-fluorophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid amide

MS APCI (+) m/z 354, 356 (M+, Br pattern) detected; ¹H NMR (400 mHz.CD₃OD) δ 8.14 (s, 1H), 7.33 (dd, 1H), 7.20 (d, 1H), 6.63 (m, 1H), 3.58(s, 3H), 1.75 (s, 3H).

Example 66

4-(4-Bromo-2-fluorophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid (2-hydroxyethoxy)-amide

MS APCI (+) m/z 414, 416 (M+, Br pattern) detected; ¹H NMR (400 mHz.CD₃OD) δ 7.93 (s, 1H), 7.33 (dd, 1H), 7.20 (d, 1H), 6.65 (m, 1H), 3.88(m, 2H), 3.68 (m, 2H), 3.57 (s, 3H), 1.83 (s, 3H).

Example 67

4-(4-Bromo-2-fluorophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid (2-hydroxy-1,1-dimethylethoxy)-amide

MS APCI (+) m/z 442, 444 (M+, Br pattern) detected; ¹H NMR (400 mHz,CD₃OD) δ 7.98 (s, 1H), 7.33 (dd, 1H), 7.20 (d, 1H), 6.62 (t, 1H), 3.59(s, 3H), 1.82 (s, 3H), 1.21 (s, 6H).

Example 68

4-(4-Bromo-2-chlorophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid (2-hydroxy-1,1-dimethylethoxy)-amide

MS APCI (−) m/z 456, 458 (M−, Cl, Br pattern) detected; ¹H NMR (400 MHz,CD₃OD) δ 8.01 (s, 1H), 7.57 (d, 1H), 7.32 (dd, 1H), 6.52 (d, 1H), 3.60(s, 3H), 3.34 (s, 2H), 1.76 (s, 3H), 1.22 (s, 6H).

Example 69

4-(4-Bromo-2-chlorophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid (2-hydroxyethoxy)-amide

MS APCI (−) m/z 428, 430 (M−, Cl, Br pattern) detected; ¹H NMR (400 MHz.CD₃OD) δ 7.98 (s, 1H), 7.57 (d, 1H), 7.32 (dd, 1H), 6.53 (d, 1H), 3.94(t, 2H), 3.71 (t, 2H), 3.58 (s, 3H), 1.76 (s, 3H).

Example 70

4-(4-Bromo-2-methylphenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid

MS APCI (−) m/z 349, 351 (M−, Br pattern) detected; ¹H NMR (400 MHz,DMSO-d₆) 9.04 (s, 1H), 8.50 (s, 1H), 7.41 (s, 1H), 7.26 (d, 1H), 6.51(d, 1H), 3.49 (s, 3H), 2.26 (s, 3H), 1.50 (s, 3H).

Example 71

4-(4-Bromo-2-methylphenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid (2-hydroxy-1,1-dimethylethoxy)-amide

MS APCI (−) m/z 436, 438 (M−, Br pattern) detected; ¹H NMR (400 MHz,CD₃OD) δ 7.96 (s, 1H), 7.34 (s, 1H), 7.20 (d, 1H), 6.50 (d, 1H), 3.58(s, 3H), 3.28 (s, 2H), 2.29 (s, 3H), 1.72 (s, 3H), 1.21 (s, 6H).

Example 72

4-(4-Bromo-2-methylphenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid cyclopropylmethoxy-amide

MS APCI (−) m/z 418, 420 (M−, Br pattern) detected; ¹H NMR (400 MHz.CD₃OD) δ 7.86 (s, 1H), 7.34 (d, 1H), 7.20 (dd, 1H), 6.52 (d, 1H), 3.57(d, 2H), 3.56 (s, 3H), 2.29 (s, 3H), 1.74 (s, 3H), 1.10 (m, 1H), 0.54(q, 2H), 0.26 (q, 2H).

Example 73

4-(4-Bromo-2-methylphenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid (2-hydroxyethoxy)-amide

MS APCI (−) m/z 408, 410 (M−, Br pattern) detected; ¹H NMR (400 MHz,CD₃OD) δ 7.91 (s, 1H), 7.34 (d, 1H), 7.20 (dd, 1H), 6.52 (d, 1H), 3.87(t, 2H), 3.68 (t, 2H), 3.56 (s, 3H), 2.30 (s, 3H), 1.74 (s, 3H).

Example 74

4-(4-Bromo-2-chlorophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid amide

MS APCI (−) m/z 368, 370 (M−, Cl, Br pattern) detected; ¹H NMR (400 MHz,CD₃OD) δ 8.16 (s, 1H), 7.57 (d, 1H), 7.32 (dd, 1H), 6.53 (d, 1H), 3.59(s, 3H), 1.70 (s, 3H).

Example 75

4-(2,4-Dichlorophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid

MS APCI (−) m/z 325, 327 (M−, Cl pattern) detected; ¹H NMR (400 MHz,DMSO-d₆) δ 9.27 (s, 1H), 8.52 (s, 1H), 7.62 (d, 1H), 7.29 (dd, 1H), 6.66(d, 1H), 3.51 (s, 3H), 1.56 (s, 3H).

Example 76

4-(4-Chloro-2-fluorophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid

MS APCI (−) m/z 309, 311 (M−, Cl pattern) detected; ¹H NMR (400 MHz,DMSO-d₆) δ 9.14 (s, 1H), 8.50 (s, 1H), 7.45 (dd, 1H), 7.16 (d, 1H), 6.74(t, 1H), 3.50 (s, 3H), 1.60 (s, 3H).

Example 77

4-(2,4-Dichlorophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid (2-hydroxyethoxy)-amide

MS APCI (−) m/z 384, 386 (M−, Cl pattern) detected; ¹H NMR (400 MHz,CD₃OD) δ 7.98 (s, 1H), 7.45 (d, 1H), 7.19 (dd, 1H), 6.60 (d, 1H), 3.94(t, 2H), 3.71 (t, 2H), 3.58 (s, 3H), 1.76 (s, 3H).

Example 78

4-(4-Chloro-2-fluorophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid (2-hydroxyethoxy)-amide

MS APCI (−) m/z 368, 370 (M−, Cl pattern) detected; ¹H NMR (400 MHz,CD₃OD) δ 7.93 (s, 1H), 7.20 (dd, 1H), 7.07 (d, 1H), 6.71 (t, 1H), 3.88(t, 2H), 3.68 (t, 2H), 3.57 (s, 3H), 1.82 (s, 3H).

Example 79

4-(4-Bromo-2-fluorophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid methoxy-amide

MS APCI (−) m/z 382, 384 (M−, Br pattern) detected; ¹H NMR (400 MHz,CD₃OD) δ 7.90 (s, 1H), 7.33 (m, 1H), 7.20 (m, 1H), 6.66 (1, 1H), 3.65(s, 3H), 3.57 (s, 3H), 1.83 (s, 3H).

Example 80

4-(4-Bromo-2-fluorophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid ethoxy-amide

MS APCI (−) m/z 396, 398 (M−, Br pattern) detected; ¹H NMR (400 MHz,CD₃OD) δ 7.90 (s, 1H), 7.33 (dd, 1H), 7.20 (m, 1H), 6.65 (t, 1H), 3.83(q, 2H), 3.57 (s, 3H), 1.83 (s, 3H), 1.22 (t, 3H).

Example 81

4-(4-Chloro-2-fluorophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid cyclopropylmethoxy-amide

MS APCI (−) m/z 378, 380 (M−, Cl pattern) detected; ¹H NMR (400 MHz.CD₃OD) δ 7.88 (s, 1H), 7.20 (d, 1H), 7.07 (d, 1H), 6.72 (t, 1H), 3.58(d, 2H), 3.57 (s, 3H), 1.83 (s, 3H), 1.10 (m, 1H), 0.54 (q, 2H), 0.26(q, 2H).

Example 82

4-(2-Fluoro-4-iodophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid (2-hydroxyethoxy)-amide

MS APCI (−) m/z 460 (M−1) detected; ¹H NMR (400 MHz, CD₃OD) δ 7.92 (s,1H), 7.46 (d, 1H), 7.37 (d, 1H), 6.50 (t, 1H), 3.86 (t, 2H), 3.68 (t,2H), 3.57 (s, 3H), 1.83 (s, 3H).

Example 83

(R)-4-(2-Fluoro-4-iodophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid (2,3-dihydroxypropoxy)-amide

MS APCI (−) m/z 490 (M−1) detected; ¹H NMR (400 MHz, CD₃OD) δ 7.93 (s,1H), 7.47 (d, 1H), 7.37 (d, 1H), 6.50 (t, 1H), 3.90 (m, 1H), 3.80 (m,2H), 3.57 (s, 3H), 3.56 (m, 2H), 1.82 (s, 3H).

Example 84

4-(2,4-Dichlorophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid cyclopropylmethoxy-amide

MS APCI (−) m/z 394, 396 (M−, Cl pattern) detected; ¹H NMR (400 MHz,CD₃OD) δ 7.93 (s, 1H), 7.45 (s, 1H), 7.18 (d, 1H), 6.60 (d, 1H), 3.65(d, 2H), 3.58 (s, 3H), 1.75 (s, 3H), 1.12 (m, 1H), 0.53 (q, 2H), 0.25(q, 2H).

Example 85

4-(2,4-Dichlorophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid ethoxy-amide

MS APCI (−) m/z 368, 370 (M−, Cl pattern) detected; ¹H NMR (400 MHz,CD₃OD) δ 7.93 (s, 1H), 7.42 (d, 1H), 7.17 (dd, 1H), 6.58 (d, 1H), 3.92(q, 2H), 3.59 (s, 3H), 1.75 (s, 3H), 1.26 (t, 3H).

Example 86

4-(4-Bromo-2-fluorophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid (2-cyano-ethyl)-amide

MS APCI (−) m/z 405, 407 (M−, Br pattern) detected; ¹H NMR (400 MHz,CD₃OD) δ 8.00 (s, 1H), 7.33 (dd, 1H), 7.20 (dd, 1H), 6.65 (t, 1H), 3.59(s, 3H), 3.47 (t, 2H), 2.65 (t, 2H), 1.80 (s, 3H).

Example 87

4-(2-Fluoro-4-iodophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid ethoxy-amide

MS APCI (−) m/z 444 (M−1) detected, ¹H NMR (400 MHz, CD₃OD) δ 7.89 (s,1H), 7.46 (dd, 1H), 7.37 (dd, 1H), 6.50 (t, 1H), 3.82 (q, 2H), 3.57 (s,3H), 1.84 (s, 3H), 1.22 (t, 3H).

Example 88

4-(2-Fluoro-4-iodophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid methoxy-amide

MS APCI (−) m/z 430 (M−1) detected; ¹H NMR (400 MHz, CD₃OD) δ 7.89 (s,1H), 7.47 (dd, 1H), 7.37 (dd, 1H), 6.50 (t, 1H), 3.64 (s, 3H), 3.57 (s,3H), 1.83 (s, 3H).

Example 89

4-(4-Bromo-2-fluorophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid hydroxyamide

4-(4-Bromo-2-fluorophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid hydroxyamide was prepared from4-(4-bromo-2-fluorophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid tert-butoxy-amide by TFA deprotection as described in Example 37.MS APCI (+) m/z 370, 372 (M+, Br pattern) detected; ¹H NMR (400 MHz,CD₃OD) δ 7.88 (s, 1H), 7.32 (dd, 1H), 7.20 (dd, 1H), 6.61 (t, 1H), 3.56(s, 3H), 1.77 (s, 3H).

Example 90

4-(4-Bromo-2-fluorophenylamino)-5-fluoro-6-oxo-1-pyridin-3-ylmethyl-1,6-dihydropyridine-3-carboxylicacid

Step A: Preparation of4-(4-bromo-2-fluorophenylamino)-6-chloro-5-fluoro-nicotinic acid: nBuLi(14.7 mL, 36.7 mmol, 2.5 M solution in hexanes) was added to a stirredsolution of diisopropylamine (5.15 mL, 36.7 mmol) in THF (20 mL) at 0°C. After 20 minutes, the reaction mixture was cooled to −78° C. and asolution of 4-bromo-2-fluorophenylamine (4.65 g, 24.5 mmol) in THF (10mL) was added. After 20 minutes, a solution of4,6-dichloro-5-fluoro-nicotinic acid (Sanchez et al J Heterocyle. Chem.1993, 30 (4), 855-9) (2.57 g, 12.25 mmol) in THF (10 mL) was added.After 10 minutes, the reaction mixture was allowed to warm to roomtemperature and stirred for 1 hour. After quenching the reaction mixturewith 10% HCl (20 mL), it was extracted with ethyl acetate. The combinedorganic extracts were dried (MgSO₄) and concentrated under reducedpressure. Trituration with methylene chloride yielded 3.21 g (72%) ofclean desired product.

Step B: Preparation of4-(4-bromo-2-fluorophenylamino)-6-chloro-5-fluoro-nicotinic acid methylester: A hexanes solution of TMSCH₂N₂ (9.46 mL, 18.9 mmol) was added to4-(4-bromo-2-fluorophenylamino)-6-chloro-5-fluoro-nicotinic acid (4.59g, 12.62 mmol) in a solution of 3:1 THF:MeOH (48 mL) at 0° C. Thereaction mixture was warmed to room temperature and stirred for 1 hour.After quenching with AcOH, the reaction mixture was diluted with ethylacetate and water. The layers were separated and the organic layer waswashed with water, saturated NaHCO₃ solution and brine. The organiclayer was dried (MgSO₄) and concentrated to give 4.40 g (92%) cleandesired product.

Step C: Preparation of4-(4-bromo-2-fluorophenylamino)-5-fluoro-6-methoxy-nicotinic acid methylester: Sodium methoxide (2.20 g, 40.8 mmol) was slowly added to astirred solution of4-(4-bromo-2-fluorophenylamino)-6-chloro-5-fluoro-nicotinic acid methylester in 4:1 MeOH:THF (20 mL) at 0° C. The reaction mixture was warmedto room temperature, stirred for 17 hours and then warmed to 40° C. andstirred for 5 hours. After cooling to room temperature, the reactionmixture was quenched with water and extracted with ethyl acetate. Thecombined organic extracts were dried (MgSO₄) and concentrated underreduced pressure. The desired product, contaminated with some startingmaterial, was carried forward without purification.

Step D: Preparation of4-(4-bromo-2-fluorophenylamino)-5-fluoro-6-oxo-1,6-dihydropyridine-3-carboxylicacid methyl ester: Hydrobromic acid (5.82 mL, 51.5 mmol) was added to amixture of 4-(4-bromo-2-fluorophenylamino)-5-fluoro-6-methoxy-nicotinicacid methyl ester (0.64 g, 1.72 mmol) and acetic acid (5.9 mL, 103mmol). The reaction mixture was stirred at 90° C. for 20 minutes andthen cooled to room temperature. After water was added to the mixture, awhite precipitate formed. The white solid was collected by filtered andwashed with water and diethyl ether to yield 0.60 g (97%) clean desiredproduct.

Step E: Preparation of4-(4-bromo-2-fluorophenylamino)-5-fluoro-6-oxo-1-pyridin-3-ylmethyl-1,6-dihydropyridine-3-carboxylicacid: Lithium hydride (14 mg, 1.64 mmol) was added to a stirred solutionof4-(4-bromo-2-fluorophenylamino)-5-fluoro-6-oxo-1,6-dihydropyridine-3-carboxylicacid methyl ester (0.190 g, 0.529 mmol) in DMF (5 mL) at 0° C. Afterstirring for 30 minutes, 3-bromomethyl-pyridine hydrobromide (0.14 g,0.53 mmol) was added. The reaction mixture was warmed to roomtemperature and stirred for 16 hours. After quenching with ice water,the reaction mixture was extracted with ethyl acetate. The combinedorganic extracts were dried (MgSO₄) and concentrated under reducedpressure. Purification by Hash column chromatography (1% MeOH inmethylene chloride) yielded4-(4-bromo-2-fluorophenylamino)-5-fluoro-6-oxo-1-pyridin-3-ylmethyl-1,6-dihydropyridine-3-carboxylicacid methyl ester. The methyl ester was dissolved in 4:1 THF:MeOH (5 mL)and 1 M LiOH solution (1.1 mL) was added. After 1 hour, the reactionmixture was acidified to pH 1 with 10% aqueous HCl solution andextracted with ethyl acetate. The combined organic extracts were washedwith brine, dried (MgSO₄) and concentrated under reduced pressure.Trituration with diethyl ether gave 0.160 g (69% two step yield) cleandesired product. MS APCI (−) m/z 434, 436 (M−, Br pattern) detected; ¹HNMR (400 mHz, DMSO-d₆) 9.40 (bs, 1H), 8.65 (s, 1H), 8.61 (s, 1H), 8.51(d, 1H), 7.74 (d, 1H), 7.58 (d, 1H), 7.39 (m, 1H), 7.34 (s, 1H), 7.16(m, 1H), 0.525 (s, 1H).

Example 91

4-(4-Bromo-2-fluorophenylamino)-5-fluoro-6-oxo-1-pyridin-3-ylmethyl-1,6-dihydropyridine-3-carboxylicacid cyclopropylmethoxy-amide

Prepared as described in Example 2 from4-(4-bromo-2-fluorophenylamino)-5-fluoro-6-oxo-1-pyridin-3-ylmethyl-1,6-dihydropyridine-3-carboxylicacid. MS APCI (+) m/z 505, 507 (M+, Br pattern) detected; ¹H NMR (400mHz, DMSO) δ 11.75 (bs, 1H), 8.97 (bs, 1H), 8.63 (s, 1H), 8.53 (d, 1H),8.13 (s, 1H), 7.78 (d, 1H), 7.55 (dd, 1H), 7.40 (dd, 1H), 7.31 (d, 1H),7.07 (td, 1H), 5.14 (s, 2H), 3.64 (d, 2H), 1.08 (m, 1H), 0.52 (d, 2H),0.25 (d, 2H).

The following compounds were prepared as described in Examples 1, 2, 3,90 and 91 using the appropriate alkyl halide.

Example 92

4-(4-Bromo-2-fluorophenylamino)-5-fluoro-6-oxo-1-pyridin-3-ylmethyl-1,6-dihydropyridine-3-carboxylicacid propoxy-amide

MS APCI (+) m/z 493, 495 (M+, Br pattern) detected; ¹H NMR (400 mHz,CD₃OD) δ 8.62 (s, 1H), 8.51 (d, 1H), 8.03 (s, 1H), 7.88 (d, 1H), 7.44(dd, 1H), 7.36 (dd, 1H), 7.27 (d, 1H), 7.02 (td, 1H), 5.24 (s, 2H), 3.82(t, 2H), 1.68 (m, 2H), 0.97 (t, 3H).

Example 93

4-(4-Bromo-2-fluorophenylamino)-5-fluoro-6-oxo-1-pyridin-2-ylmethyl-1,6-dihydropyridine-3-carboxylicacid

MS APCI (−) m/z 434, 436 (M−, Br pattern) detected; ¹H NMR (400 mHz,DMSO) δ 9.40 (s, 1H), 8.56 (s, 1H), 8.51 (d, 1H), 7.79 (t, 1H), 7.59 (d,1H), 7.34 (m, 3H), 7.15 (m, 1H), 5.29 (s, 2H).

Example 94

4-(4-Bromo-2-fluorophenylamino)-1-cyclopropylmethyl-5-fluoro-6-oxo-1-pyridin-2-ylmethyl-1,6-dihydropyridine-3-carboxylicacid

MS APCI (−) m/z 397, 399 (M−, Br pattern) detected; ¹H NMR (400 mHz,DMSO) δ 9.35 (bs, 1H), 8.46 (s, 1H), 7.59 (d, 1H), 7.36 (d, 1H), 7.13(td, 1H), 3.85 (d, 2H), 1.23 (m, 1H), 0.50 (d, 2H), 0.39 (d, 2H).

Example 95

4-(4-Bromo-2-fluorophenylamino)-1-cyclopropylmethyl-5-fluoro-6-oxo-1,6-dihydropyridine-3-carboxylicacid (2-hydroxy-1,1-dimethylethoxy)-amide

MS APCI (+) m/z 486, 488 (M+, Br pattern) detected; ¹H NMR (400 mHz,DMSO) δ 8.02 (s, 1H), 7.56 (d, 1H), 7.32 (d, 1H), 7.04 (td, 1H), 3.79(d, 2H), 3.28 (s, 2H), 1.28 (m, 1H), 1.17 (s, 6H), 0.52 (d, 2H), 0.43(d, 2H).

Example 96

4-(4-Bromo-2-fluorophenylamino)-1-cyclopropylmethyl-5-fluoro-6-oxo-1,6-dihydropyridine-3-carboxylicacid amide

MS APCI (+) m/z 398, 400 (M+, Br pattern) detected; ¹H NMR (400 mHz.DMSO) δ 10.04 (s, 1H), 8.22 (s, 1H), 8.05 (bs, 1H), 7.66 (bs, 1H), 7.56(d, 1H), 7.33 (d, 1H), 7.04 (td, 1H), 3.75 (d, 2H), 1.27 (m, 1H), 0.51(d, 2H), 0.43 (d, 2H).

Example 97

4-(4-Bromo-2-fluorophenylamino)-5-fluoro-6-oxo-1-pyridin-2-ylmethyl-1,6-dihydropyridine-3-carboxylicacid cyclopropylmethoxy-amide

MS APCI (+) m/z 505, 507 (M+, Br pattern) detected; ¹H NMR (400 mHz,DMSO) δ 11.71 (bs, 1H), 9.04 (bs, 1H), 8.52 (d, 1H), 8.07 (s, 1H), 7.80(t, 1H), 7.56 (d, 1H), 7.31 (m, 3H), 7.07 (td, 1H), 5.21 (s, 2H), 3.63(d, 2H), 1.07 (m, 1H), 0.51 (q, 2H), 0.24 (q, 2H).

Example 98

4-(4-Bromo-2-fluorophenylamino)-5-fluoro-6-oxo-1-pyridin-2-ylmethyl-1,6-dihydropyridine)-3-carboxylicacid (2-hydroxy-1,1-dimethylethoxy)-amide

MS APCI (+) m/z 523, 525 (M+, Br pattern) detected; ¹H NMR (400 mHz,DMSO) δ 11.23 (bs, 1H), 8.86 (bs, 1H), 8.53 (d, 1H), 8.18 (s, 1H), 7.80(t, 1H), 7.56 (d, 1H), 7.31 (m, 3H), 7.08 (td, 1H), 5.25 (s, 2H), 3.28(s, 2H), 1.56 (s, 6H).

Example 99

1-Benzyl-4-(4-bromo-2-fluorophenylamino)-5-fluoro-6-oxo-1,6-dihydropyridine-3-carboxylicacid

MS APCI (+) m/z 433, 435 (M+, Br pattern) detected; ¹H NMR (400 mHz,DMSO-D₆)δ 9.35 (s, 1H), 8.54 (s, 1H), 7.59 (dd, 1H), 7.35 (m, 6H), 7.15(m, 1H), 5.22 (s, 2H).

Example 100

1-Benzyl-4-(4-bromo-2-fluorophenylamino)-5-fluoro-6-oxo-1,6-dihydropyridine-3-carboxylicacid amide

MS APCI (−) m/z 432, 434 (M−, Br pattern) detected; ¹H NMR (400 mHz,CD₃OD) δ 7.18 (s, 1H), 7.36 (m, 6H), 7.27 (d, 1H), 7.02 (m, 1H), 5.20(s, 2H),

Example 101

1-Benzyl-4-(4-bromo-2-fluorophenylamino)-5-fluoro-6-oxo-1,6-dihydropyridine-3-carboxylicacid cyclopropylmethoxy-amide

MS APCI (−) m/z 502, 504 (M−, Br pattern) detected; ¹H NMR (400 mHz,CD₃OD) δ 7.89 (s, 1H), 7.34 (m, 7H), 7.27 (d, 1H), 7.02 (m, 1H), 5.19(s, 2H), 3.65 (d, 2H), 1.11 (m, 1H), 0.55 (m, 2H), 0.26 (m, 2H).

Example 102

1-Benzyl-4-(4-bromo-2-fluorophenylamino)-5-fluoro-6-oxo-1,6-dihydropyridine-3-carboxylicacid (2-hydroxyethoxy)-amide

MS APCI (−) m/z 492, 494 (M−, Br pattern) detected; ¹H NMR (400 mHz,CD₃OD) δ 7.96 (s, 1H), 7.36 (m, 7H), 7.27 (d, 1H), 7.04 (m, 1H), 5.19(s, 2H), 3.96 (t, 2H), 3.73 (t, 2H).

Example 103

1-Benzyl-4-(4-bromo-2-fluorophenylamino)-5-fluoro-6-oxo-1,6-dihydropyridine-3-carboxylicacid (2-amino-ethoxy)-amide hydrogen chloride

1-Benzyl-4-(4-bromo-2-fluorophenylamino)-5-fluoro-6-oxo-1,6-dihydropyridine-3-carboxylicacid (2-amino-ethoxy)-amide was prepared by deprotecting4(2-{[1-benzyl-4-(4-bromo-2-fluorophenylamino)-5-fluoro-6-oxo-1,6-dihydropyridine-3-carbonyl]-aminooxy}-ethyl)-carbamicacid tert-butyl ester under standard conditions; MS APCI (+) m/z 493,495 (M+, Br pattern) detected; ¹H NMR (400 mHz, CD₃OD) δ 8.03 (s, 1H),7.36 (m, 6H), 7.29 (d, 1H), 7.04 (td, 1H), 5.20 (s, 2H), 4.12 (t, 2H),3.17 (t, 2H).

Example 104

4-(4-Bromo-2-fluorophenylamino)-1-cyclohexylmethyl-5-fluoro-6-oxo-1,6-dihydropyridine-3-carboxylicacid

MS APCI (−) m/z 439, 441 (M−, Br pattern) detected; ¹H NMR (400 mHz,CD₃D) δ 8.21 (s, 1H), 7.32 (dd, 1H), 7.27 (d, 1H), 7.05 (td, 1H), 3.88(d, 2H), 1.85 (m, 1H), 1.79 (m, 2H), 1.69 (m, 3H), 1.25 (m, 3H), 1.05(q, 2H).

Example 105

4-(4-Bromo-2-fluorophenylamino)-1-cyclohexylmethyl-5-fluoro-6-oxo-1,6-dihydropyridine-3-carboxylicacid (2-hydroxy-1,1-dimethylethoxy)-amide

MS APCI (+) m/z 528, 530 (M+, Br pattern) detected; ¹H NMR (400 mHz,CD₃OD) δ 7.85 (s, 1H), 7.36 (d, 1H), 7.28 (d, 1H), 7.02 (td, 1H), 3.86(d, 2H), 3.42 (s, 2H), 1.88 (m, 1H), 1.76 (m, 2H), 1.67 (m, 3H), 1.29(m, 3H), 1.26 (s, 6H), 1.06 (m, 2H), 0.90 (m, 2H).

Example 106

4-(4-Bromo-2-fluorophenylamino)-1-cyclohexylmethyl-5-fluoro-6-oxo-1,6-dihydropyridine-3-carboxylicacid cyclopropylmethoxy-amide

MS APCI (+) m/z 510, 512 (M+, Br pattern) detected; ¹H NMR (400 mHz,CD₃OD) δ 7.76 (s, 1H), 7.36 (d, 1H), 7.28 (d, 1H), 7.02 (td, 1H), 3.84(d, 2H), 3.69 (d, 2H), 1.86 (m, 1H), 1.75 (m, 2H), 1.66 (m, 2H), 1.26(m, 3H), 1.07 (m, 2H), 0.90 (m, 2H), 0.58 (d, 2H), 0.29 (d, 2H).

Example 107

4-(4-Bromo-2-fluorophenylamino)-5-fluoro-1-(2-methoxyethyl)-6-oxo-1,6-dihydropyridine-3-carboxylicacid

MS APCI (−) m/z 401, 403 (M−, Br pattern) detected; ¹H NMR (400 mHz,CD₃OD) δ 8.32 (s, 1H), 7.38 (dd, 1H), 7.31 (d, 1H), 7.10 (td, 1H), 4.21(t, 2H), 3.66 (t, 2H), 3.35 (s, 3H).

Example 108

4-(4-Bromo-2-fluorophenylamino)-5-fluoro-1-(2-methoxyethyl)-6-oxo-1,6-dihydropyridine-3-carboxylicacid cyclopropylmethoxy-amide

MS APCI (+) m/z 472, 474 (M+, Br pattern) detected; ¹H NMR (400 mHz,CD₃OD) δ 7.79 (s, 1H), 7.36 (dd, 1H), 7.28 (dd, 1H), 7.03 (td, 1H), 4.18(t, 2H), 3.68 (m, 4H), 3.35 (s, 3H), 1.15 (m, 1H), 0.59 (q, 2H), 0.30(q, 2H).

Example 109

4-(4-Bromo-2-fluorophenylamino)-5-fluoro-1-(2-hydroxyethyl)-6-oxo-1,6-dihydropyridine-3-carboxylicacid cyclopropylmethoxy-amide

4-(4-Bromo-2-fluorophenylamino)-5-fluoro-1-(2-hydroxyethyl)-6-oxo-1,6-dihydropyridine-3-carboxylicacid cyclopropylmethoxy-amide was prepared by deprotecting4-(4-bromo-2-fluorophenylamino)-1-[2-(tert-butyl-dimethylsilanyloxy)-ethyl]-5-fluoro-6-oxo-1,6-dihydropyridine-3-carboxylicacid cyclopropylmethoxy-amide under standard conditions. MS APCI (+) m/z458, 460 (M+, Br pattern) detected; ¹H NMR (400 mHz. CD₃OD) δ 7.82 (s,1H), 7.35 (dd, 1H), 7.27 (d, 1H), 7.02 (m, 1H), 4.11 (t, 2H), 3.84 (t,2H), 3.72 (m, 2H), 1.16 (m, 1H), 0.59 (m, 2H), 0.31 (m, 2H).

Example 110

4-(4-Bromo-2-fluorophenylamino)-1-(2-cyclopropylethyl)-5-fluoro-6-oxo-1,6-dihydropyridine-3-carboxylicacid

MS APCI (−) m/z 411, 413 (M−, Br pattern) detected; ¹H NMR (400 mHz,CD₃OD) δ 8.37 (s, 1H), 7.34 (dd, 1H), 7.27 (d, 1H); 7.04 (td, 1H), 4.10(t, 2H), 1.62 (q, 2H), 0.67 (m, 1H), 0.43 (q, 2H), 0.01 (q, 2H).

Example 111

4-(4-Bromo-2-fluorophenylamino)-5-fluoro-1-(2-morpholin-4-yl-ethyl)-6-oxo-1,6-dihydropyridine-3-carboxylicacid

MS ESI (+) m/z 458, 460 (M+, Br pattern) detected; ¹H NMR (400 mHz.DMSO) δ 8.34 (s, 1H), 7.58 (d, 1H), 7.35 (d, 1H), 7.10 (td, 1H), 4.10(t, 2H), 3.56 (m, 4H), 3.17 (m, 2H), 2.62 (m, 2H).

Example 112

4-(4-Bromo-2-fluorophenylamino)-5-fluoro-1-(1-methyl-1H-imidazol-4-ylmethyl)-6-oxo-1,6-dihydropyridine-3-carboxylicacid

¹H NMR (400 mHz. DMSO) δ 9.37 (s, 1H), 8.68 (bs, 1H), 8.60 (s, 1H), 7.60(d, 1H), 7.56 (s, 1H), 7.37 (d, 1H), 7.14 (td, 1H), 5.20 (s, 2H), 3.77(s, 3H).

Example 113

4-(4-Bromo-2-fluorophenylamino)-1-(2-cyclopropylethyl)-5-fluoro-6-oxo-1,6-dihydropyridine-3-carboxylicacid amide

MS APCI (+) m/z 412, 414 (M+, Br pattern) detected; ¹H NMR (400 mHz,CD₃OD) δ 8.12 (s, 1H), 7.35 (dd, 1H), 7.28 (d, 1H), 7.02 (td, 1H), 4.10(t, 2H), 1.76 (q, 2H), 0.72 (m, 1H), 0.47 (q, 2H), 0.05 (q, 2H).

Example 114

4-(4-Bromo-2-fluorophenylamino)-5-fluoro-1-(2-morpholin-4-yl-ethyl)-6-oxo-1,6-dihydropyridine-3-carboxylicacid cyclopropylmethoxy-amide

MS APCI (+) m/z 527, 529 (M+, Br pattern) detected; ¹H NMR (400 mHz.CD₃OD) δ 7.85 (s, 1H), 7.36 (d, 1H), 7.28 (d, 1H), 7.03 (td, 1H), 4.13(t, 2H), 3.68 (m, 6H), 2.71 (t, 2H), 2.55 (m, 4H), 1.17 (m, 1H), 0.59(q, 2H), 0.31 (q, 2H).

Example 115

4-(4-Bromo-2-fluorophenylamino)-5-fluoro-1-(1-methyl-1H-imidazol-4-ylmethyl)-6-oxo-1,6-dihydropyridine-3-carboxylicacid cyclopropylmethoxy-amide

MS APCI (+) m/z 508, 510 (M+, Br pattern) detected; ¹H NMR (400 mHz.CD₃OD) δ 7.98 (s, 1H), 7.62 (s, 1H), 7.34 (dd, 1H), 7.26 (dd, 1H), 7.16(s, 1H), 7.0 (td, 1H), 5.04 (s, 2H), 3.72 (d, 2H), 3.70 (s, 3H), 1.18(m, 1H), 0.59 (q, 2H), 0.31 (q, 2H).

Example 116

4-(4-Bromo-2-fluorophenylamino)-1-(2-cyclopropylethyl)-5-fluoro-6-oxo-1,6-dihydropyridine-3-carboxylicacid (2-hydroxyethoxy)-amide

MS APCI (+) m/z 472, 474 (M+, Br pattern) detected; ¹H NMR (400 mHz,CD₃OD) δ 7.90 (s, 1H), 7.36 (d, 1H), 7.28 (d, 1H), 7.02 (td, 1H), 4.09(t, 2H), 3.98 (t, 2H), 3.75 (t, 2H), 1.66 (q, 2H), 0.72 (m, 1H), 0.47(q, 2H), 0.06 (q, 2H).

Example 117

4-(4-Bromo-2-fluorophenylamino)-5-fluoro-1-(1H-imidazol-4-ylmethyl)-6-oxo-1,6-dihydropyridine-carboxylicacid cyclopropylmethoxy-amide

MS APCI (+) m/z 494, 496 (M+, Br pattern) detected; ¹H NMR (400 mHz,CD₃OD) δ 7.99 (s, 1H), 7.70 (s, 1H), 7.35 (dd, 1H), 7.26 (d, 1H), 7.20(s, 1H), 7.0 (td, 1H), 5.10 (s, 2H), 3.72 (d, 2H), 1.16 (m, 1H), 0.59(q, 2H), 0.31 (q, 2H).

Example 118

4-(4-Bromo-2-fluorophenylamino)-5-fluoro-6-oxo-1-pyridin-2-ylmethyl-1,6-dihydropyridine-3-carboxylicacid (2-hydroxyethoxy)-amide

MS APCI (+) m/z 495, 497 (M+, Br pattern) detected; ¹H NMR (400 mHz,CD₃OD) δ 8.52 (d, 1H), 8.08 (s, 1H), 7.84 (t, 1H), 7.44 (d, 1H), 7.36(m, 2H), 7.27 (d, 1H), 7.04 (td, 1H), 5.27 (s, 2H), 4.0 (t, 2H), 3.75(t, 2H).

Example 119

4-(4-Bromo-2-fluorophenylamino)-5-fluoro-1-(6-methylpyridin-2-ylmethyl)-6-oxo-1,6-dihydropyridine-3-carboxylicacid cyclopropylmethoxy-amide

MS APCI (+) m/z 519, 521 (M+, Br pattern) detected; ¹H NMR (400 mHz.CD₃OD) δ 8.03 (s, 1H), 7.70 (t, 1H), 7.36 (d, 1H), 7.28 (d, 1H), 7.21(d, 1H), 7.16 (d, 1H), 7.04 (td, 1H), 5.22 (s, 2H), 3.70 (d, 2H), 2.52(s, 3H), 1.17 (m, 1H), 0.58 (q, 2H), 0.30 (q, 2H).

Example 120

4-(4-Bromo-2-fluorophenylamino)-5-fluoro-1-(6-methyl-pyridin-2-ylmethyl)-6-oxo-1,6-dihydropyridine-3-carboxylicacid methoxy-amide

MS APCI (+) m/z 479, 481 (M+, Br pattern) detected; ¹H NMR (400 mHz,CD₃OD) δ 8.05 (s, 1H), 7.69 (t, 1H), 7.36 (dd, 1H), 7.28 (d, 1H), 7.21(d, 1H), 7.14 (d, 1H), 7.04 (td, 1H), 5.22 (s, 2H), 3.75 (s, 3H), 2.52(s, 3H).

Example 121

4-(4-Bromo-2-fluorophenylamino)-5-fluoro-6-oxo-1-pyridin-3-ylmethyl-1,6-dihydropyridine-3-carboxylicacid (3-aminopropoxy)-amide hydrogen chloride

4-(4-Bromo-2-fluorophenylamino)-5-fluoro-6-oxo-1-pyridin-3-ylmethyl-1,6-dihydropyridine-3-carboxylicacid (3-aminopropoxy)-amide was prepared by deprotecting(3-{[4-(4-bromo-2-fluorophenylamino)-5-fluoro-6-oxo-1-pyridin-3-ylmethyl-1,6-dihydropyridine-3-carbonyl]-aminooxy}-propyl)-carbamicacid ten-butyl ester under standard conditions. MS APCI (+) m/z 508, 510(M+, Br pattern) detected; ¹H NMR (400 mHz. DMSO) δ 9.01 (s, 1H), 8.92(m, 2H), 8.61 (d, 1H), 8.29 (s, 1H), 8.12 (m, 1H), 7.81 (m, 2H), 7.57(d, 1H), 7.35 (d, 1H), 7.22 (td, 1H), 5.34 (s, 2H), 3.97 (t, 2H), 3.01(q, 2H), 1.91 (m, 2H).

Example 122

4-<4-Bromo-2-fluorophenylamino)-5-fluoro-6-oxo-1-pyrazin-2-ylmethyl-1,6-dihydropyridine-3-carboxylicacid

MS APCI (−) m/z 435, 437 (M−, Br pattern) detected; ¹H NMR (400 mHz.DMSO) δ 9.42 (bs, 1H), 8.71 (s, 1H), 8.63 (s, 1H), 8.58 (s, 2H), 7.59(dd, 1H); 7.36 (d, 1H), 7.15 (td, 1H), 5.39 (s, 2H).

Example 123

4-(4-Bromo-2-fluorophenylamino)-5-fluoro-6-oxo-1-pyrazin-2-ylmethyl-1,6-dihydropyridine-3-carboxylicacid cyclopropylmethoxy-amide

MS APCI (+) m/z 506, 508 (M+, Br pattern) detected; ¹H NMR (400 mHz.CD₃OD) δ 8.72 (s, 1H), 8.57 (s, 1H), 8.55 (s, 1H), 8.05 (s, 1H), 7.36(dd, 1H), 7.28 (d, 1H), 7.04 (td, 1H), 5.33 (s, 2H), 3.70 (d, 2H), 1.56(m, 1H), 0.59 (q, 2H), 0.30 (q, 2H).

Example 124

4-(4-Bromo-2-fluorophenylamino)-5-fluoro-6-oxo-1-pyrazin-2-ylmethyl-1,6-dihydropyridine-3-carboxylicacid ethoxy-amide

MS APCI (+) m/z 480, 482 (M+, Br pattern) detected; ¹H NMR (400 mHz,CD₃OD) δ 8.71 (s, 1H), 8.57 (s, 1H), 8.55 (s, 1H), 8.07 (s, 1H), 7.36(dd, 1H), 7.28 (d, 1H), 7.04 (td, 1H), 5.33 (s, 2H), 3.95 (q, 2H), 1.28(t, 3H).

Example 125

4-(4-Bromo-2-fluorophenylamino)-5-fluoro-6-oxo-1-pyrazin-2-ylmethyl-1,6-dihydropyridine-3-carboxylicacid propoxy-amide

MS APCI (+) m/z 494, 496 (M+, Br pattern) detected; ¹H NMR (400 mHz,CD₃OD) δ 8.72 (s, 1H), 8.58 (s, 1H), 8.55 (s, 1H), 8.07 (s, 1H), 7.36(dd, 1H), 7.28 (d, 1H), 7.04 (td, 1H), 5.34 (s, 2H), 3.84 (t, 2H), 1.69(m, 2H), 0.98 (t, 3H).

Example 126

4-(4-Bromo-2-fluorophenylamino)-5-fluoro-6-oxo-1-pyridazin-3-ylmethyl-1,6-dihydropyridine-3-carboxylicacid cyclopropylmethoxy-amide

MS APCI (+) m/z 506, 508 (M+, Br pattern) detected; ¹H NMR (400 mHz.CD₃OD)δ 9.14 (d, 1H), 8.10 (s, 1H), 7.80 (m, 1H), 7.74 (m, 1H), 7.36(dd, 1H), 7.27 (d, 1H), 7.05 (td, 1H), 5.46 (s, 2H), 3.70 (d, 2H), 1.17(m, 1H), 0.58 (q, 2H), 0.30 (q, 2H).

Example 127

4-(4-Bromo-2-fluorophenylamino)-5-fluoro-6-oxo-1-pyrimidin-4-ylmethyl-1,6-dihydropyridine-3-carboxylicacid cyclopropylmethoxy-amide

MS APCI (+) m/z 506, 508 (M+, Br pattern) detected; ¹H NMR (400 mHz,CD₃OD) δ 9.09 (s, 1H), 8.75 (d, 1H), 8.0 (s, 1H), 7.48 (d, 1H), 7.38 (d,1H), 7.29 (d, 1H), 7.07 (td, 1H), 5.30 (s, 2H), 3.69 (d, 2H), 1.16 (m,1H), 0.58 (q, 2H), 0.30 (q, 2H).

Example 128

4-(4-Bromo-2-fluorophenylamino)-5-fluoro-1-methanesulfonylmethyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid cyclopropylmethoxy-amide

Step A:4-(4-Bromo-2-fluorophenylamino)-5-fluoro-1-methylsulfanylmethyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid methyl ester was prepared as previously described usingchloromethylsulfanylmethane as the electrophile.

Step B:4-(4-Bromo-2-fluorophenylamino)-5-fluoro-1-methanesulfonylmethyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid methyl ester was prepared from4-(4-bromo-2-fluorophenylamino)-5-fluoro-1-methylsulfanylmethyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid methyl ester as follows. A solution of Oxone® (84 mg, 0.14 mmol) inwater (2 mL) was added dropwise to a stirred solution of4-(4-bromo-2-fluorophenylamino)-5-fluoro-1-methylsulfanylmethyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid methyl ester (38 mg, 0.091 mmol) in MeOH (2 mL) at roomtemperature. After 4 days stirring, the reaction mixture was dilutedwith water (20 mL), extracted with ethyl acetate dried (MgSO₄) andconcentrated under reduced pressure. Purification by flash columnchromatography (0.5% MeOH in methylene chloride) gave clean desiredproduct (25 mg, 61%).

Step C:4-(4-Bromo-2-fluorophenylamino)-5-fluoro-1-methanesulfonylmethyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid cyclopropylmethoxy-amide was prepared from4-(4-bromo-2-fluorophenylamino)-5-fluoro-1-methanesulfonylmethyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid methyl ester, as previously described. MS APCI (+) m/z 506, 508(M+, Br pattern) detected; ¹H NMR (400 mHz. CD₃OD) δ 7.84 (s, 1H), 7.31(dd, 1H), 7.27 (d, 1H), 7.04 (td, 1H), 5.37 (s, 2H), 3.78 (d, 2H), 3.06(s, 3H), 1.21 (m, 1H), 0.63 (q, 2H), 0.33 (q, 2H).

Example 129

4-(4-Bromo-2-fluorophenylamino)-5-fluoro-6-oxo-1,6-dihydropyridine-3-carboxylicacid

A stirred solution of4-(4-bromo-2-fluorophenylamino)-5-fluoro-6-oxo-1,6-dihydropyridine-3-carboxylicacid methyl ester (0.10 g, 0.278 mmol) in 4:1 THF:MeOH (5 mL) wastreated with 1 M LiOH solution (0.75 mL). After 8 hours, the reactionmixture was acidified to pH 1 with 1 N HCl and extracted with ethylacetate. The combined organic extracts were washed with brine, dried(MgSO₄) and concentrated under reduced pressure to give 0.095 g (99%) ofdesired product as a white solid. MS APCI (−) m/z 343, 345 (M−, Brpattern) detected; ¹H NMR (400 mHz, DMSO) δ 12.34 (bs, 1H), 9.39 (bs,1H), 7.95 (s, 1H), 7.59 (d, 1H), 7.36 (d, 1H), 7.12 (td, 1H).

Example 130

4-(4-Bromo-2-fluorophenylamino)-5-fluoro-6-oxo-1,6-dihydropyridine-3-carboxylicacid cyclopropylmethoxy-amide

Prepared as described in Example 2 from4-(4-bromo-2-fluorophenylamino)-5-fluoro-6-oxo-1,6-dihydropyridine-3-carboxylicacid. MS APCI (+) m/z 414, 416 (M+, Br pattern) detected; ¹H NMR (400mHz, DMSO) δ 9.15 (bs, 1H), 7.59 (s, 1H), 7.55 (dd, 1H), 7.32 (d, 2H),7.02 (td, 1H), 3.64 (d, 2H), 1.07 (m, 1H), 0.50 (q, 2H), 0.24 (q, 2H).

Example 131

5-(5-Amino-[1,3,4]oxadiazol-2-yl)-4-(4-bromo-2-fluorophenylamino)-3-fluoro-1-methyl-1H-pyridin-2-one

Step A: Preparation of4-(4-bromo-2-fluorophenylamino)-5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid hydrazide: A mixture of4-(4-bromo-2-fluorophenylamino)-5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid (70 mg, 0.195 mmol), EDCl (112 mg, 0.585 mmol), and HOBt (79 mg,0.585 mmol) in DMF (3 mL) was stirred for 30 minutes. Hydrazine (19 mg,0.585 mmol) was added followed by Et₃N (0.082 mL, 0.585 mmol). After 3hours, the reaction mixture was diluted with EtOAc and washed withsaturated NH₄Cl solution, saturated NaHCO₃ solution and brine. Theorganic layer was dried (MgSO₄) and concentrated to yield 64 mg (89%)desired product.

Step B: Preparation of5-(5-amino-[1,3,4]oxadiazol-2-yl)-4-(4-bromo-2-fluorophenylamino)-3-fluoro-1-methyl-1H-pyridin-2-one:Cyanogen bromide (36 mg, 0.31 mmol) was added to a suspension of4-(4-bromo-2-fluorophenylamino)-5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid hydrazide (63 mg, 0.169 mmol) in dioxane (2 mL) followed by anaqueous NaHCO₃ (2 mL of a 0.09 M solution) solution. After 17 hours,additional cyanogen bromide (14 mg) was added. After 19; hours, thereaction mixture was diluted with water and extracted with ethylacetate. The combined organic extracts were washed with brine, dried(MgSO₄) and concentrated under reduced pressure. Crystallization(MeOH:THF) followed by trituration (Et₂O:MeOH 5:1) gave clean desiredproduct as a white solid (60 mg, 89%). MS APCI (+) m/z 398, 400 (M+, Brpattern) detected; ¹H NMR (400 mHz, CD₃OD) δ 8.06 (s, 1H), 7.37 (d, 1H),7.31 (d, 1H), 7.10 (td, 1H), 3.64 (s, 3H).

The following compounds were prepared similarly using the appropriatecarboxylic acid.

Example 132

5-(5-Amino-[1,3,4]oxadiazol-2-yl)-4-(4-chloro-2-fluorophenylamino)-3-fluoro-1-methyl-1H-pyridin-2-one

MS APCI (+) m/z 354, 356 (M+, Cl pattern) detected; ¹H NMR (400 mHz,CD₃OD) δ 8.06 (s, 1H), 7.23 (d, 1H), 7.16 (s, 2H), 3.64 (s, 3H).

Example 133

5-(5-Amino-[1,3,4]oxadiazol-2-yl)-4-(4-bromo-2-fluorophenylamino)-3-fluoro-1-pyrazin-2-ylmethyl-1H-pyridin-2-one

MS APCI (+) m/z 476, 478 (M+, Br pattern) detected; ¹H NMR (400 mHz,CD₃OD) δ 8.75 (s, 1H), 8.58 (s, 1H), 8.55 (s, 1H), 8.26 (s, 1H), 7.35(dd, 1H), 7.29 (d, 1H), 7.09 (td, 1H), 5.40 (s, 2H).

Example 134

5-(5-Amino-[1,3,4]oxadiazol-2-yl)-4-(4-bromo-2-fluorophenylamino)-1,3-dimethyl-1H-pyridin-2-one

MS APCI (−) m/z 392, 394 (M−, Br pattern) detected; ¹H NMR (400 MHz,CD₃OD) δ 8.14 (s, 1H), 7.36 (d, 1H), 7.23 (d, 1H), 6.72 (t, 1H), 3.63(s, 3H), 1.78 (s, 3H).

Example 135

5-(5-Amino-[1,3,4]oxadiazol-2-yl)-4-(4-bromo-2-methylphenylamino)-3-fluoro-methyl-1H-pyridin-2-one

MS APCI (+) m/z 394, 396 (M+, Br pattern) detected; ¹H NMR (400 mHz,CD₃OD) δ 8.05 (s, 1H), 7.39 (s, 1H), 7.30 (d, 1H), 6.95 (dd, 1H), 3.62(s, 3H), 2.31 (s, 3H).

Example 136

4-(4-Bromo-2-fluorophenylamino)-1,3-dimethyl-5-(5-oxo-4,5-dihydro-[1,3,4]oxadiazol-2-yl)-1H-pyridin-2-one

1,1′-Carbonyldiimidazole (275 mg, 1.70 mmol) was added to a stirredsolution of4-(4-bromo-2-fluorophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid hydrazide (728 mg, 1.62 mmol (82% pure material)) in DMF (2 mL).After 1 hour, the reaction mixture was diluted with ethyl acetate andwashed with brine. Some of the product precipitated and was collected byfiltration. The filtrate was diluted with 1 N HCl and the layersseparated. The aqueous layer was extracted with ethyl acetate. Thecombined organic extracts were washed with brine, dried (MgSO4) andconcentrated under reduced pressure. The resulting residue wastriturated with diethyl ether to give the desired product which wascombined with the earlier obtained product. The combined yield of cleandesired product was 482 mg (75%): MS APCI (−) m/z 393, 395 (M−, Brpattern) detected; ¹H NMR (400 MHz, DMSO-d₆) δ 8.22 (s, 1H), 7.88 (s,1H), 7.50 (dd, 1H), 7.21 (d, 1H), 6.59 (t, 1H), 3.52 (s, 3H), 1.76 (s,3H).

Example 137

4-(4-Bromo-2-fluorophenylamino)-5-[5-(2-hydroxyethylamino)-[1,3,4]oxadiazol-2-yl]-1,3-dimethyl-1H-pyridin-2-one

Ethanolamine (0.037 mL, 0.61 mmol) was added to a suspension of4-(4-bromo-2-fluorophenylamino)-1,3-dimethyl-5-(5-oxo-4,5-dihydro-[1,3,4]oxadiazol-2-yl)-1H-pyridin-2-one(81 mg, 0.20 mmol) in EtOH (2 mL). The reaction mixture was healed to90° C. with stirring for 17 hours. After cooling to room temperature,the reaction mixture was concentrated under reduced pressure andpurified by flash column chromatography (5% MeOH in methylene chlorideincreasing to 20% MeOH in 5% steps) to give the desired intermediateadduct (58 mg, 62%). The intermediate (56 mg, 0.12 mmol) was suspendedin 2:1 methylene chloride:MeCN (4.5 mL) and PPh₃ (98 mg, 0.37 mmol).Et₃N (0.14 mL, 1.0 mmol) and CCl₄ (0.036 mL, 0.37 mmol) were added. Theresulting mixture was healed to 55° C. with stirring for 30 minutes.After cooling to room temperature, the reaction mixture was diluted withethyl acetate and washed with brine. The aqueous layer was extractedwith ethyl acetate. The organic layers were combined, washed with brine,dried (MgSO₄) and concentrated under reduced pressure. Purification byHash column chromatography (ethyl acetate) gave clean desired product(24 mg, 45%): MS APCI (−) m/z 436, 438 (M−, Br pattern) detected; ¹H NMR(400 MHz, CD₃OD) δ 8.14 (s, 1H), 7.36 (dd, 1H), 7.22 (dd, 1H), 6.71 (t,1H), 3.71 (t, 2H), 3.63 (s, 3H), 3.41 (t, 2H), 1.79 (s, 3H).

The following compounds were prepared similarly using the appropriateamine. In some instances a final standard deprotection step wasrequired.

Example 138

4-(4-Bromo-2-fluorophenylamino)-1,3-dimethyl-5-[5-(2-methylaminoethylamino)-[1,3,4]oxadiazol-2-yl]-1H-pyridin-2-one

MS APCI (−) m/z 449, 451 (M−, Br pattern) detected; ¹H NMR (400 MHz,CD₃OD) δ 8.18 (s, 1H), 7.37 (dd, 1H), 7.23 (d, 1H), 6.71 (t, 1H), 3.66(t, 2H), 3.64 (s, 3H), 329 (t, 2H), 2.75 (s, 3H), 1.80 (s, 3H).

Example 139

5-[5-(2-Amino-ethylamino)-[1,3,4]oxadiazol-2-yl]-4-(4-bromo-2-fluorophenylamino)-1,3-dimethyl-1H-pyridin-2-one

MS APCI (+) m/z 437, 439 (M+, Br pattern) detected; ¹H NMR (400 MHz.CD₃OD) δ 8.20 (s, 1H), 7.37 (dd, 1H), 7.23 (dd, 1H), 6.71 (t, 1H), 3.65(s, 3H), 3.63 (t, 2H), 3.22 (t, 2H), 1.80 (s, 3H).

Example 140

4-<4-Bromo-2-fluorophenylamino)-3-fluoro-5-[5-(2-hydroxyethylamino)-[1,3,4]oxadiazol-2-yl]-1-methyl-1H-pyridin-2-one

MS APCI (+) m/z 442, 444 (M+, Br pattern) detected; ¹H NMR (400 mHz,CD₃OD) δ 8.06 (s, 1H), 7.35 (dd, 1H), 7.29 (d, 1H), 7.08 (td, 1H), 3.75(t, 2H), 3.65 (s, 3H), 3.47 (t, 2H).

Example 141

5-[5-(2-Amino-ethylamino)-[1,3,4]oxadiazol-2-yl]-4-(4-bromo-2-fluorophenylamino)-3-fluoro-1-methyl-1H-pyridin-2-onehydrogen chloride

MS APCI (+) m/z 441, 443 (M+, Br pattern) detected; ¹H NMR (400 mHz,DMSO) δ 8.94 (s, 1H), 8.17 (s, 1H), 8.06 (t, 1H), 7.95 (bs, 3H), 7.59(dd, 1H), 7.36 (d, 1H), 7.12 (td, 1H), 3.57 (s, 3H), 3.51 (q, 2H), 3.05(q, 2H).

Example 142

4-(4-Bromo-2-fluorophenylamino)-1,3-dimethyl-5-(1H-tetrazol-5-yl)-1H-pyridin-2-one

Step A: Preparation of3-{5-[4-(4-bromo-2-fluorophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydro-pyridin-3-yl]-tetrazol-1-yl}-propionitrile:PPh₃ (83 mg, 0.32 mmol) was added to a stirred suspension of4-(4-bromo-2-fluorophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid (2-cyano-ethyl)-amide (51 mg; 0.12 mmol) in MeCN (1.5 mL). DIAD(0.065 mL, 0.31 mmol) and TMSN₃ (0.045 mL, 0.32) were added dropwise.After 22 hours, the reaction mixture was diluted with ethyl acetate andwashed with water. The aqueous layer was extracted with ethyl acetate.The combined organic extracts were dried (MgSO₄) and concentrated underreduced pressure. Purification by flash column chromatography gave cleandesired product (33 mg, 61%).

Step B: Preparation of4-(4-bromo-2-fluorophenylamino)-1,3-dimethyl-5-(1H-tetrazol-5-yl)-1H-pyridin-2-one:DBU (0.030 mL, 0.21 mmol) was added to a solution of3-{5-[4-(4-bromo-2-fluorophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydro-pyridin-3-yl]-tetrazol-1-yl}-propionitrile(30 mg, 0.069 mmol) in methylene chloride (1.5 mL). After 2 hours, thereaction mixture was diluted with ethyl acetate and washed with 1 N HCl.The aqueous layer was extracted with ethyl acetate. The combined organicextracts were washed with brine, dried (MgSO₄) and concentrated underreduced pressure. Trituration with diethyl ether gave clean desiredproduct (20 mg, 77%); MS APCI (−) m/z 377, 379 (M−, Br pattern)detected; ¹H NMR (400 MHz, CD₃OD) δ 8.20 (s, 1H), 7.29 (dd, 1H), 7.13(dd, 1H), 6.63 (t, 1H), 3.65 (s, 3H), 1.91 (s, 3H).

Example 143

4-(4-Bromo-2-fluorophenylamino)-3-fluoro-1-methyl-5-(5-methyl-4H-[1,2,4]triazol-3-yl)-1H-pyridin-2-one

Step A: Preparation of4-(4-bromo-2-fluorophenylamino)-5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid N′-(1-imino-ethyl)-hydrazide: Ethyl acetimidate HCl salt (40 mg,0.32 mmol) and Et₃N (0.049 mL, 0.35 mmol) were added to a stirredsuspension of4-(4-bromo-2-fluorophenylamino)-5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid hydrazide (0.10 g, 0.27 mmol) in 2:1 THF:DMF (3 mL) at 0° C. After1.5 hours at 0° C. and 17 hours at room temperature, the reactionmixture was poured onto water, neutralized with dilute aqueous HCl andextracted with ethyl acetate. The combined organic extracts were dried(MgSO₄) and concentrated under reduced pressure. Trituration withmethylene chloride gave the desired product.

Step B: Preparation of4-(4-bromo-2-fluorophenylamino)-3-fluoro-1-methyl-5-(5-methyl-4H-[1,2,4]triazol-3-yl)-1H-Pyridin-2-one:PPh₃ (0.12 g, 0.45 mmol), Et₃N (0.17 mL, 1.21 mmol), and CCl₄ (0.044 mL,0.45 mmol) were added to a stirred suspension of4-(4-bromo-2-fluorophenylamino)-5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid N′-(1-imino-ethyl)-hydrazide (6.073 g, 0.18 mmol) in methylenechloride (2 mL). The reaction mixture was stirred al 50° C. for 2 hours.After cooling to room temperature, the reaction mixture was diluted withethyl acetate, washed with water, dried (MgSO₄) and concentrated.Purification by flash column chromatography (4% MeOH in methylenechloride) gave clean desired product (30 mg, 50%); MS APCI (−) m/z 394,396 (M−, Br pattern) detected; ¹H NMR (400 mHz, CD₃OD) δ 8.16 (s, 1H),7.31 (dd, 1H), 7.25 (d, 1H), 7.01 (td, 1H), 3.67 (s, 3H), 2.51 (s, 3H).

Example 144

5-(5-Amino-[1,3,4]thiadiazol-2-yl)-4-(4-bromo-2-fluorophenylamino)-3-fluoro-1-methyl-1H-pyridin-2-one

A mixture of4-(4-bromo-2-fluorophenylamino)-5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid (200 mg, 0.557 mmol), EDCl (214 mg, 1.11 mmol) and HOBt (151 mg,1.11 mol) were stirred in DMF (10 mL) for 30 minutes. Thiosemicarbazide(51 mg, 0.562 mmol) and Et₃N (0.116 mL, 1.5 mmol) were added. After 1hour, the reaction mixture was diluted with saturated aqueous NH₄Cl, andextracted with ethyl acetate. The combined organic extracts were dried(MgSO₄) and concentrated under reduced pressure. Purification by flashcolumn chromatography (5% to 10% MeOH in methylene chloride) gave 70 mgpartially pure intermediate adduct. PPh₃ (78 mg, 0.30 mmol), Et₃N (0.10mL, 0.74 mmol), and CCl₄ (0.029 mL, 0.30 mmol) were added to a stirredsuspension of intermediate adduct (40 mg, 0.093 mmol) in 1:1 methylenechloride:MeCN (4 mL). The reaction mixture was heated to 50° C. for 5hours. After cooling to room temperature, the reaction mixture wasdiluted with ethyl acetate, washed with water, dried (MgSO₄) andconcentrated under reduced pressure. Purification by flash columnchromatography (twice) (4% MeOH in methylene chloride) gave cleandesired product (10 mg, 33%): MS APCI (+) m/z 414, 416 (M+, Br pattern)detected; ¹H NMR (400 mHz. CD₃OD) δ 7.80 (s, 1H), 7.31 (dd, t H), 7.25(d, 1H), 7.02 (td, 1H), 3.64 (s, 3H).

Example 145

5-(5-Amino-4H-[1,2,4]triazol-3-yl)-4-(4-bromo-2-fluorophenylamino)-3-fluoro-1-methyl-1H-pyridin-2-one

A mixture of4-(4-bromo-2-fluorophenylamino)-5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid hydrazide (100 mg, 0.268 mmol). 10% aqueous HCl (0.19 mL) andcyanamide (0.04 mL, 0.515 mmol) was heated to reflux for 3 days. Thereaction mixture was concentrated under reduced pressure, diluted withwater and washed with water. DMF (10 mL) was added to the aqueous layerand it was extracted with methylene chloride. The combined organicextracts were dried (MgSO₄) and concentrated under reduced pressure togive the desired intermediate adduct (35 mg). PPh₃ (76 mg, 0.29 mmol),Et₃N (0.10 mL, 0.74 mmol), and CCl₄ (0.028 mL, 0.29 mmol) were added toa stirred suspension of intermediate adduct (30 mg, 0.072 mmol) inmethylene chloride (2 mL). The reaction mixture was healed to 50° C. for5 hours. After cooling to room temperature, the reaction mixture wasdiluted with ethyl acetate, washed with water, dried (MgSO₄) andconcentrated under reduced pressure. Purification by flash columnchromatography (4% MeOH in methylene chloride) followed by methylenechloride trituration gave clean desired product (1 mg, 4%); MS APCI (+)m/z 397, 399 (M+, Br pattern) detected.

Example 146

N-[4-(4-Bromo-2-fluorophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carbonyl]-C-phenyl-methanesulfonamide

N-[4-(4-Bromo-2-fluorophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carbonyl]-C-phenyl-methanesulfonamidewas prepared from4-(4-bromo-2-fluorophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid as follows. To a solution of4-(4-bromo-2-fluorophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid (0.040 mg, 0.113 mmol) in DMF (1.5 mL) was added1,1′-carbonyldiimidazole (0.074 mg, 0.456 mmol). After stirring for twohours, α-toluenesulfonamide (0.079 mg, 0.461 mmol) was added, followedby DBU (0.070 mL, 0.459 mmol). After stirring for 16 hours at roomtemperature, the reaction mixture was diluted with EtOAc and 1N HClsolution. The organic layer was separated and washed with brine. Theaqueous layer was extracted with EtOAc (2×) and washed with brine. Thecombined organic extracts were dried (MgSO₄) and concentrated underreduced pressure. Purification by flash column chromatography (2% MeOHin methylene chloride) gave 0.039 g (68%) clean desired product; MS APCI(−) m/z 506, 508 (M−, Br pattern) detected; ¹H NMR (400 MHz, CD₃OD) δ8.29 (s, 1H), 7.27 (m, 3H), 7.18 (d, 1H), 7.11 (m, 3H), 6.56 (t, 1H),4.44 (s, 2H), 3.54 (s, 3H), 1.62 (s, 3H).

Example 147

N-[4-(4-Bromo-2-fluorophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carbonyl]-methanesulfonamide

N-[4-(4-Bromo-2-fluorophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carbonyl]-methanesulfonamidewas prepared from4-(4-bromo-2-fluorophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid as follows. To a solution of4-(4-bromo-2-fluorophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid (0.041 mg, 0.115 mmol) in DMF (1 mL) was added1,1′-carbonyldiimidazole (0.039 mg, 0.241 mmol). After stirring for twohours, methanetoluenesulfonamide (0.023 mg, 0.242 mmol) was added,followed by DBU (0.035 mL, 0.230 mmol). After stirring 16 hours at roomtemperature, the reaction mixture was diluted with EtOAc and 1N HClsolution. The organic layer was separated and washed with brine. Theaqueous layer was extracted with EtOAc (2×) and washed with brine. Thecombined organic extracts were dried (MgSO₄) and concentrated underreduced pressure. Purification by (lash column chromatography (15% MeOHin methylene chloride) gave 0.028 g (57%) clean desired product: MS APCI(−) m/z 430, 432 (M−, Br pattern) detected; ¹H NMR (400 MHz, DMSO-d₆) δ11.13 (s, 1H), 8.25 (s, 1H), 7.49 (dd, 1H), 7.23 (d, 1H), 6.55 (t, 1H),3.46 (s, 3H), 2.83 (s, 3H), 1.56 (s, 3H).

Example 148

4-(2-Fluoro-4-methylphenylamino)-1,2,5-trimethyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid cyclopropylmethoxy-amide

Step A: Preparation of4-hydroxy-1,2,5-trimethyl-6-oxo-1,6-dihydropyridine-3-carboxylic acidethyl ester: A mixture of 2-methyl-3-oxo-pentanedioic acid diethyl ester(10.0 g, 46.3 mmol), 1,1-diethoxy-ethene (12.8 mL, 92.5 mmol) and sodiummethoxide (0.026 mg, 0.481 mmol) was heated to 85° C. for nine hours.The reaction mixture was cooled to room temperature and concentrated. Tothe resulting residue was added methylamine (1.91 mL, 55.5 mmol), 40%H₂O). After stirring at room temperature for 16 hours, the reactionmixture was diluted with diethyl ether and washed with water. Theaqueous phase was acidified to pH 1 with 10% HCl solution and extractedwith EtOAc. The organic layer was dried (MgSO₄) and concentrated.Trituration of the resulting residue with diethyl ether and flash columnchromatography (3% MeOH in methylene chloride) gave 3.55 g (34%) desiredproduct.

Step B: Preparation of4-Chloro-1,2,5-trimethyl-6-oxo-1,6-dihydropyridine-3-carboxylic acidethyl ester: Phosphorous oxychloride (20.0 mL, 216 mmol) was added to4-hydroxy-1,2,5-trimethyl-6-oxo-1,6-dihydropyridine-3-carboxylic acidethyl ester and heated to 80° C. After two hours, the reaction mixturewas concentrated under reduced pressure. The resulting residue waspoured onto ice and carefully neutralized with saturated NaHCO₃, anddiluted with EtOAc. After stirring for 16 hours, the organic layer wasseparated and the aqueous layer was reextracted with EtOAc repeatedly.The pH of the aqueous layer was adjusted to pH 11 with saturated K₂CO₃and extracted with EtOAc (2×). The combined organic extracts were dried(MgSO₄) and concentrated under reduced pressure to give 3.42 g (89%)clean desired product.

Step C: Preparation of4-(2-fluoro-4-methylphenylamino)-1,2,5-trimethyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid ethyl ester: 2-Fluoro-4-methylphenylamine (0.259 g, 2.07 mmol),palladium (II) acetate (0.046 g, 0.205 mmol),rac-2,2-bis(diphenylphosphino)-1,1′-binaphthyl (0.192 g, 0.308 mmol),and cesium carbonate (1.00 g, 3.08 mmol) were added to a solution of4-chloro-1,2,5-trimethyl-6-oxo-1,6-dihydropyridine-3-carboxylic acidethyl ester (0.50 g, 2.05 mmol) in toluene (7 mL) in a sealed vial.After stirring 10 minutes, the mixture was heated to 80° C. After 24hours, the reaction mixture was cooled to room temperature and dilutedwith EtOAc. The resulting precipitate was filtered and washed withEtOAc. The filtrate was diluted with EtOAc and washed with water. Theaqueous layer was reextracted with EtOAc. The combined organic layerswere washed with brine, dried (Na₂SO₄) and concentrated. Purification byflash column chromatography (20:1 methylene chloride/MeOH) gave 0.048 g(71%) desired product.

Step D: Preparation of4-(2-fluoro-4-methylphenylamino)-1,2,5-trimethyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid cyclopropylmethoxy-amide: O-cyclopropylmethyl-hydroxylamine (0.046g, 0.527 mmol) was added to a solution of4-(2-fluoro-4-methylphenylamino)-1,2,5-trimethyl-fi-oxo-1,6-dihydropyridine-3-carboxylicacid ethyl ester (0.070 g, 0.211 mmol) in THF (2 mL). The solution wascooled to 0° C. and lithium bis(trimethylsilyl)amide (1.05 mL, 1 Msolution in hexanes) was added dropwise. The reaction mixture was warmedto room temperature. After stirring for 1 hour, the reaction wasquenched by addition of a saturated aqueous solution of NaHCO₃ andpartitioned between EtOAc and brine. The aqueous layer was reextractedwith EtOAc. The combined organic extracts were dried (Na₂SO₄) andconcentrated. Purification by flash column chromatography (30:1methylene chloride/MeOH) gave 0.032 g (40%) desired product as a yellowsolid; MS ESI (+) m/z 374 (M+1) detected; ¹H NMR (400 MHz, CD₃OD) δ 6.91(d, 1H), 6.83 (d, 1H), 6.63 (t, 1H), 3.59 (s, 3H), 3.47 (d, 2H), 2.41(s, 3H), 2.27 (s, 3H), 1.86 (s, 3H) 0.99 (m, 1H) 0.48 (m, 2H) 0.18 (m,2H), ¹⁹F (376 MHz, CD₃OD)-132.1 (s, 1F).

Example 149

4-(2-Fluoro-4-methylphenylamino)-1,2,5-trimethyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid (2-hydroxyethoxy)-amide

4-(2-Fluoro-4-methylphenylamino)-1,2,5-trimethyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid (2-hydroxyethoxy)-amide was prepared as described in Example 148using the appropriate hydroxylamine, followed by deprotection usingstandard literature methods. MS ESI (+) m/z 364 (M+1) detected; ¹H NMR(400 MHz, CD₃OD) δ 6.91 (d, 1H), 6.83 (d, 1H), 6.63 (t, 1H), 3.80 (m,2H), 3.63 (m, 2H), 3.60 (s, 3H), 2.42 (s, 3H), 2.27 (s, 3H) 1.85 (s,3H), ¹⁹F (376 MHz, CD₃OD) −127.8 (s, 1F).

Example 150

4-(2-Fluoro-4-methylphenylamino)-1,3-dimethyl-6,7-dihydro-1H-pyrrolo[3,4-b]pyridine-2,5-dione

Step A: Preparation of2-bromomethyl-4-(2-fluoro-4-methylphenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid ethyl ester: To a solution of4-(2-fluoro-4-methylphenylamino)-1,2,5-trimethyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid ethyl ester (0.150 g, 0.451 mmol) in DMF (5 mL) was addedN-bromosuccinimide (0.084 g, 0.474 mmol). After stirring for 30 minutes,the reaction mixture was diluted with EtOAc, washed with water andbrine, dried (Na₂SO₂) and concentrated under reduced pressure to yield ayellow residue. Purification by flash column chromatography (methylenechloride) gave 0.122 g (66%) of a yellow residue.

Step B: Preparation of4-(2-fluoro-4-methylphenylamino)-1,3-dimethyl-6,7-dihydro-1H-pyrrolo[3,4-b]pyridine-2,5-dione:To a solution of2-bromomethyl-4-(2-fluoro-4-methylphenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid ethyl ester (0.016 g, 0.040 mmol) in MeOH (0.50 mL) was addedammonia (0.006 mL, 0.040 mmol, 7M solution in MeOH). After stirring for2 hours at room temperature, the reaction mixture was heated to 40° C.for 8 hours. The resulting white precipitate was filtered to yield cleandesired product (0.005 g, 46%). MS ESI (+) m/z 303 (M+1) detected; ¹HNMR (400 MHz, DMSO) δ 8.16 (br s, 1H), 8.04 (br s, 1H), 6.81-6.94 (m,3H), 4.33 (s, 2H), 3.45 (s, 3H), 2.33 (s, 3H), 1.63 (s, 3H), ¹⁹F (376MHz, DMSO)-127.1 (s, 1F).

Example 151

4-(4-Bromo-2-fluorophenylamino)-6-oxo-1-phenyl-1,6-dihydropyridazine-3-carboxylicacid cyclopropylmethoxy-amide

Step A: Preparation of 3-oxo-2-(phenyl-hydrazono)-pentanedioic aciddimethyl ester: 3-oxo-2-(phenyl-hydrazono)-pentanedioic acid dimethylester was prepared from 3-oxo-pentanedioic acid dimethyl ester (7.02 mL,45.9 mmol) according to the procedure of Schober et al. (J. HeterocylicChem. 1989, 26, 169) to give 8.81 g (72%) of the desired product.

Step B: Preparation of4-hydroxy-6-oxo-1-phenyl-1,6-dihydropyridazine-3-carboxylic acid methylester: A mixture of 3-oxo-2-(phenyl-hydrazono)-pentanedioic aciddimethyl ester (4.38 g, 15.7 mmol) in 1,2-dichlorobenzene (15 mL) wasrefluxed. After 20 hours, the reaction mixture was concentrated underreduced pressure to give 3.83 g (99%) of the desired product.

Step C: Preparation of4-chloro-6-oxo-1-phenyl-1,6-dihydropyridazine-3-carboxylic acid methylester: A mixture of4-hydroxy-6-oxo-1-phenyl-1,6-dihydropyridazine-3-carboxylic acid methylester (3.83 g, 15.6 mmol) and phosphorous oxychloride (50 mL) was healedto 85° C. After 20 hours, the reaction mixture was concentrated underreduced pressure. The resulting residue was quenched with water. Theprecipitate was filtered and dissolved in EtOAc, dried (MgSO₄) andconcentrated under reduced pressure to yield 3.44 g (84%) of desiredproduct.

Step D: Preparation of4-(4-bromo-2-fluorophenylamino)-6-oxo-1-phenyl-1,6-dihydropyridazine-3-carboxylicacid: To a mixture of4-chloro-6-oxo-1-phenyl-1,6-dihydropyridazine-3-carboxylic acid methylester (0.250 g, 0.944 mmol) in 1,2-dichlorobenzene (3.8 mL) was added4-bromo-2-fluoro aniline (0.561 g, 3.78 mmol), and cesium carbonate(0.615 mg, 1.89 mmol). The reaction mixture was heated to reflux. After1 hour, the reaction mixture was cooled to room temperature. Water wasadded and the mixture was diluted with EtOAc. The aqueous layer wasseparated, acidified with 10% HCl solution, and extracted with EtOAc.The combined organic layers were dried (MgSO₄), concentrated underreduced pressure, and triturated to give 0.153 g (43%) of the desiredproduct.

Step E. Preparation of4-(4-Bromo-2-fluorophenylamino)-6-oxo-1-phenyl-1,6-dihydropyridazine-3-carboxylicacid cyclopropylmethoxy-amide,4-(4-Bromo-2-fluorophenylamino)-6-oxo-1-phenyl-1,6-dihydropyridazine-3-carboxylicacid cyclopropylmethoxy-amide was prepared from4-(4-bromo-2-fluorophenylamino)-6-oxo-1-phenyl-1,6-dihydropyridazine-3-carboxylicacid as described in Example 2. MS APCI (−) m/z 471, 473 (M−, Brpattern) detected; ¹H NMR (400 MHz, CD₃OD-CDCl₃) δ 7.50 (m, 8H), 6.12(s, 1H), 3.78 (d, 2H), 1.18 (m, 1H), 0.59 (q, 2H), 0.32 (q, 2H).

Example 152

4-(4-Bromo-2-fluorophenylamino)-6-oxo-1-phenyl-1,6-dihydropyridazine-3-carboxylicacid (2-hydroxyethoxy)-amide

Prepared from4-(4-bromo-2-fluorophenylamino)-6-oxo-1-phenyl-1,6-dihydropyridazine-3-carboxylicacid as described in Example 3, MS APCI (−) m/z 461, 463 (M−, Brpattern) detected; ¹H NMR (400 MHz, CD₃OD) δ 7.51 (m, 8H), 6.09 (s, 1H),4.04 (t, 2H), 3.77 (t, 2H).

Example 153

2-(4-Bromo-2-fluorophenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid

Step A. Preparation of 2-chloro-6-oxo-1,6-dihydropyridine-3-carboxylicacid: 2-Chloro-6-oxo-1,6-dihydropyridine-3-carboxylic acid was preparedfrom dichloronicotinic acid (3.00 g, 15.6 mmol, Aldrich) according tothe procedure described in U.S. Pat. No. 3,682,932 (1972) to yield 1.31g (48%) of the desired product.

Step B. Preparation of2-chloro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid methylester: To a solution of 2-chloro-6-oxo-1,6-dihydropyridine-3-carboxylicacid (0.644 g, 3.71 mmol) in DMF (20 mL) was added lithium hydride (95%,0.078 g, 9.28 mmol) and the reaction mixture was stirred for 40 minutesunder N₂. Methyl iodide (0.508 mL, 1.16 g, 8.16 mmol) was then added andthe reaction mixture was stirred for an additional 45 minutes. Thereaction mixture was quenched with 2 M HCl until the pH was 6-7. Thereaction mixture was diluted with EtOAc and saturated NaCl and thelayers separated. The aqueous layer was back extracted with EtOAc (1×).The combined organic layers were dried (Na₂SO₄) and concentrated underreduced pressure to yield a crude yellow solid. HPLC analysis showed twoproducts in a 4:1 ratio that were separated by flash columnchromatography (methylene chloride/EtOAc, 15:1 to 10:1) to give 0.466 g(62%) pure desired product as a white crystalline solid. The minorproduct was also isolated as a pale yellow crystalline solid andidentified as the regioisomer 2-chloro-6-methoxy-nicotinic acid methylester.

Step C. Preparation of2-(4-bromo-2-fluorophenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid methyl ester: To a solution of 4-bromo-2-fluorophenylamine (0.192g, 1.01 mmol) in THF (5 mL) at −78° C. under N₂ was added lithiumbis(trimethylsilyl)amide (1.50 mL, 1.50 mmol, 1 M solution in hexanes)dropwise. The reaction mixture was stirred for one hour at −78° C.2-Chloro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid methylester (0.202 g, 1.00 mmol) was then added dropwise as a solution in THF(5 mL) and the reaction mixture was stirred for one hour at −78° C. Thereaction mixture was quenched by the addition of H₂O and the pH wasadjusted to pH 7 with saturated NH₄Cl and then diluted with EtOAc. Theorganic layer was separated and washed with saturated NaCl, dried(Na₂SO₄), and concentrated under reduced pressure. Purification by flashcolumn chromatography (methylene chloride/EtOAc, 15:1) gave 0.232 g(65%) pure desired product as a while crystalline solid.

Step D. Preparation of2-(4-bromo-2-fluorophenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid: To a solution of2-(4-bromo-2-fluorophenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid methyl ester in MeOH (1.5 mL) was added 1 M NaOH (800 uL, 0.902mmol). The reaction mixture was stirred at 60° C. for 4 hours and thenal room temperature for 16 hours. The reaction mixture was diluted withH₂O, acidified with 2 M HCl until the pH was 1-2, and then diluted withEtOAc. The organic layer was separated and washed with saturated NaCl,dried (Na₂SO₄), and concentrated under reduced pressure to yield 0.053 g(97%) desired product as a pale orange solid. MS ESI (+) m/z 341, 343(M+, Br pattern) detected; ¹H NMR (400 MHz, DMSO-d₆) δ 13.08 (s, 1H),10.0 (s, 1H), 7.87 (d, 1H), 7.65 (d, 1H), 7.35 (d, 1H), 6.95 (t, 1H),6.16 (d, 1H), 3.19 (s, 3H).

In the foregoing examples, a variety of anilines can be used in place of4-bromo-2-fluorophenylamine in Step C of Example 153.

Example 154

2-(4-Bromo-2-fluorophenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid cyclopropylmethoxy-amide

A mixture of2-(4-bromo-2-fluorophenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid (0.022 g, 0.064 mmol), EDCl (0.019 g, 0.097 mmol), and HOBt (0.019g, 0.097 mmol) in DMA (1 mL) was stirred for 30 minutes at roomtemperature under N₂. O-Cyclopropylmethyl-hydroxylamine (0.017 g, 0.19mmol) was added followed by Et₃N (0.022 mL, 0.016 g, 0.16 mmol). Afterthe reaction mixture was stirred for 16 hours at room temperature, itwas diluted with EtOAc and washed with saturated NH₄Cl solution,saturated NaHCO₃ solution and saturated NaCl. The organic layer wasdried (Na₂SO₄) and concentrated under reduced pressure. Purification byflash column chromatography (methylene chloride/methanol, 20:1) gave0.015 g (57%) pure desired product as a yellow solid. MS APCI (−) m/z410, 411 (M−, Br pattern) detected; ¹H NMR (400 MHz, DMSO-d₆) δ 11.4 (s,1H), 9.81 (s, 1H), 7.58 (m, 2H), 7.28 (d, 1H), 6.82 (t, 1H), 6.17 (d,1H), 3.46 (d, 2H), 3.22 (s, 3H), 0.99 (m, 1H), 0.48 (m, 2H), 0.18 (m,2H).

Example 155

2-(2-Fluoro-4-methylphenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid (2-hydroxyethoxy)-amide

Step A. Preparation of2-(2-fluoro-4-methylphenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid (2-vinyloxyethoxy)-amide: To a solution of2-(2-fluoro-4-methylphenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid methyl ester (0.050 g, 0.17 mmol) in THF (1.5 mL) under N₂ wasadded O-(2-vinyloxy-ethyl)-hydroxylamine (0.044 g, 0.43 mmol). Thesolution was cooled to 0° C. and lithium bis(trimethylsilyl)amide (0.86mL, 0.86 mmol, 1 M solution in hexanes) was added dropwise. The reactionmixture was warmed to room temperature. After stirring for 40 minutes,the reaction mixture was quenched by the addition of NaHCO₃ andpartitioned between EtOAc and saturated NaCl. The layers were separatedand the aqueous layer was reextracted with EtOAc. The combined organicextracts were dried (Na₂SO₄) and concentrated under reduced pressure.Purification by flash column chromatography (methylenechloride/methanol, 20:1) gave 0.048 g (77%) pure desired product as anoff-white foamy solid.

Step B. Preparation of2-(2-fluoro-4-methylphenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid (2-hydroxyethoxy)-amide: To a solution of2-(2-fluoro-4-methylphenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid (2-vinyloxyethoxy)-amide (0.048 g, 0.13 mmol) in ethanol (5 mL) wasadded aqueous 2 M HCl (0.332 mL, 0.664 mmol). The reaction mixture wasstirred for 16 hours at room temperature. The pH of the reaction mixturewas adjusted with 1 M NaOH until 7. The reaction mixture was dilutedwith EtOAc and H₂O. The organic layer was separated and washed withsaturated NaCl, dried (Na₂SO₄), and concentrated under reduced pressureto yield 0.044 g (100%) pure desired product as a pale yellow foamysolid. MS ESI (+) m/z 336 (M+1) detected; ¹H NMR (400 MHz, CDCl₃) δ 10.3(s, 1H), 8.46 (s, 1H), 7.38 (d, 1H), 6.96-6.87 (m, 2H), 6.76 (t, 1H),6.18 (d, 1H), 4.04 (m, 2H), 3.93 (br s, 1H), 3.75 (br s, 2H), 3.20 (s,3H), 2.33 (s, 3H).

Any of the hydroxylamines used in the foregoing examples can be coupledas described in Example 154 or Example 155. In some instances, a finaldeprotection step may be required. These deprotections can beaccomplished by standard literature methods. Example 155 is one suchexample in which a final deprotection step is required.

Example 156

2-(4-Bromo-2-fluorophenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid (2-hydroxyethoxy)-amide

Step A. Preparation of2-(4-bromo-2-fluorophenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid (2-vinyloxyethoxy)-amide:2-(4-Bromo-2-fluorophenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid (0.020 g, 0.059 mmol) was coupled as described previously inExample 154 using O-(2-vinyloxy-ethyl)-hydroxylamine to yield 0.015 g(60%) pure desired product as a yellow solid.

Step B. Preparation of2-(4-Bromo-2-fluorophenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid (2-hydroxyethoxy)-amide:2-(4-Bromo-2-fluorophenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid (2-vinyloxyethoxy)-amide (0.015 g, 0.035 mmol) was deprotected asdescribed previously in Step B of Example 155 to yield 0.010 g (70%)pure desired product as a dark yellow solid. MS ESI (+) m/z 400, 402(M+, Br pattern) detected; ¹H NMR (400 MHz, CDCl₃) δ 10.3 (s, 1H), 9.11(s, 1H), 7.47 (d, 1H), 7.32 (d, 1H), 7.23 (d, 1H), 6.70 (t, 1H), 6.22(d, 1H), 4.04 (br s, 2H), 3.75 (br s, 2H) 3.24 (s, 3H).

Example 157

2-(2-Fluoro-4-iodophenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid methoxy-amide

2-(2-Fluoro-4-iodophenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid methyl ester was coupled as described previously in Example 155using O-methyl-hydroxylamine. MS ESI (+) m/z 418 (M+1) detected.

Example 158

2-(4-Bromo-2-fluorophenylamino)-1-ethyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid (2-hydroxyethoxy)-amide

2-Chloro-6-oxo-1,6-dihydropyridine-3-carboxylic acid was converted to2-(4-bromo-2-fluorophenylamino)-1-ethyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid methyl ester following the procedures described in Steps B-C ofExample 153 using ethyl iodide in Step B of Example 153.2-(4-Bromo-2-fluorophenylamino)-1-ethyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid methyl ester was then coupled as described in Example 155 to yieldthe desired product as a tan solid. MS APCI (+) m/z 414, 416 (M+, Brpattern) detected; ¹H NMR (400 MHz, CD₃OD) δ 7.59 (d, 1H), 7.38 (d, 1H),7.24 (d, 1H), 6.77 (t, 1H), 6.33 (d, 1H), 4.16 (q, 2H), 3.73 (m, 2H),3.59 (m, 2H), 1.21 (t, 3H).

Example 159

2-(4-Bromo-2-fluorophenylamino)-5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid (2-hydroxyethoxy)-amide

2,6-Dichloro-5-fluoro-nicotinic acid (Lancaster Synthesis) was convertedto2-(4-bromo-2-fluorophenylamino)-5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid methyl ester following the procedures described in Steps A-C ofExample 153.2-(4-Bromo-2-fluorophenylamino)-5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid methyl ester was then coupled as described in Example 155 to yieldthe desired product as a yellow solid. MS ESI (+) m/z 418, 420 (M+, Brpattern) detected; ¹H NMR (400 MHz, CDCl₃) 7.32 (dd, 1H), 7.29-7.19 (m,2H), 6.61 (t, 1H), 4.06 (m, 2H), 3.76 (m, 2H), 3.33 (s, 3H), 3.32 (s,3H).

Example 160

5-Bromo-2-(4-bromo-2-fluorophenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid

Step A. Preparation of5-bromo-2-(4-bromo-2-fluorophenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid methyl ester: To a solution of2-(4-bromo-2-fluorophenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid methyl ester (0.390 g, 1.34 mmol) in DMF (10 mL) was addedN-bromosuccinimide (0.263, 1.48 mmol). The reaction mixture was stirredat room temperature for 25 minutes and then quenched with saturatedsodium bisulfite. The reaction mixture was diluted with H₂O andpartitioned between EtOAc/diethyl ether and saturated NaCl. The layerswere separated and the aqueous layer was reextracted with EtOAc (1×).The combined organic layers were dried (Na₂SO₄) and concentrated underreduced pressure. Purification by flash column chromatography (methylenechloride/EtOAc, 15:1) gave 0.424 g (85%) pure desired product as alavender foamy solid.

Step B. Preparation of5-bromo-2-(4-bromo-2-fluorophenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid: To a suspension of5-bromo-2-(4-bromo-2-fluorophenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid methyl ester (0.030 g, 0.069 mmol) in methanol (1 mL) was added 1 MNaOH (0.346 mL, 0.346 mmol). The reaction mixture was heated to 60° C.for 12 hours. The reaction mixture was diluted with H₂O and the pH wasadjusted with 1 M HCl until 1-2. Solids precipitated out of solution,which were collected, washed with H₂O and dried under vacuum to yield0.021 g (72%) pure desired product as a pale yellow solid. MS ESI (+)m/z 421, 423 (M+3 Br pattern) detected; ¹H NMR (400 MHz. DMSO-d₆) δ 13.3(br s, 1H), 9.93 (s, 1H), 8.21 (s, 1H), 7.66 (d, 1H), 7.34 (d, 1H), 7.05(t, 1H), 3.18 (s, 3H).

Example 161

5-Bromo-2-(4-bromo-2-fluorophenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid (2-hydroxyethoxy)-amide

5-Bromo-2-(4-bromo-2-fluorophenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid (0.018 g, 0.043 mmol) was converted to the desired productfollowing the procedures described in Example 156 to yield 0.009 g (45%)pure desired product as a dark yellow solid. MS ESI (+) m/z 480, 482(M+, Br pattern) detected; ¹H NMR (400 MHz. CDCl₃) δ 8.00 (s, 1H), 7.32(m, 1H), 7.24 (d, 1H), 6.69 (t, 1H), 3.99 (m, 2H), 3.73 (m, 2H), 3.32(s, 3H).

Example 162

2-(4-Bromo-2-fluorophenylamino)-6-oxo-1,6-dihydropyridine-3-carboxylicacid

Step A. Preparation of2-(4-bromo-2-fluorophenylamino)-6-chloro-nicotinic acid: To a solutionof 4-bromo-2-fluorophenylamine (10.4 g, 54.7 mmol) in THF (25 mL) at−78° C. under N₂ was added lithium bis(trimethylsilyl)amide (83.3 mL,83.3 mmol, 1 M solution in hexanes) dropwise over 15 minutes. Thereaction mixture was stirred for one hour at −78° C.2,6-Dichloro-nicotinic acid (5.00 g, 26.0 mmol) was then added dropwiseas a solution in THF (15 mL) and the reaction mixture was allowed towarm from −78° C. to room temperature and stir for 16 hours. Thereaction mixture was quenched by the addition of H₂O and the pH wasadjusted to 0-2 with 6 N HCl and then diluted with EtOAc. The organiclayer was separated and washed with H₂O, saturated NaCl, dried (Na₂SO₄),and concentrated under reduced pressure. The crude product wastriturated several times with ethyl acetate and the resulting solid wascollected, washed with dichloromethane and dried under vacuum to yield7.50 g (83%) pure desired product as a dark pink solid.

Step B. Preparation of2-(4-bromo-2-fluorophenylamine)-6-chloro-nicotinic acid methyl ester: Toa suspension of 2-(4-bromo-2-fluorophenylamino)-6-chloro-nicotinic acid(5.00 g, 14.5 mmol) in methanol/benzene (1:1, 100 mL) under N₂ was added(trimethylsilyl)diazomethane (2.0 M solution in hexanes) dropwise untilthe bubbling caused by gas evolution ceased. Solids precipitated out ofsolution. The reaction was allowed to stir for 1 hour. Excess(trimethylsilyl)diazomethane was quenched by the dropwise addition ofglacial acetic acid. The precipitated solids were filtered and washedwith methanol. The filtrate was concentrated to a smaller volume andadditional solids precipitated out of solution that were filtered andwashed with methanol. The solids were combined and dried under vacuum toyield 4.82 g (93%) of pure desired product as a dark pink solid.

Step C. Preparation of2-(4-bromo-2-fluorophenylamino)-6-methoxy-nicotinic acid methyl ester:To a mixture of 2-(4-bromo-2-fluorophenylamino)-6-chloro-nicotinic acidmethyl ester (2.00 g, 5.56 mmol) and sodium methoxide (0.791 g, 13.9mmol) was added MeOH (50 mL) to give a slurry that was stirred al 60-65°C. for 16 hours under N₂. Additional sodium methoxide (0.791 g, 13.9mmol) was added and the reaction mixture was allowed to stir another 3days at 60-65° C. The reaction mixture was cooled to room temperatureand glacial acetic acid was added dropwise until the pH was 7. Theresulting suspension was filtered and washed with H₂O to yield a pinksolid that was collected and dried under vacuum to yield 1.74 g (88%)pure desired product.

Step D. Preparation of2-(4-bromo-2-fluorophenylamino)-6-oxo-1,6-dihydropyridine-3-carboxylicacid methyl ester: To2-(4-bromo-2-fluorophenylamino)-6-methoxy-nicotinic acid methyl ester(1.00 g, 2.82 mmol) in a sealed flask was added glacial acetic acid (10mL) and HBr (10 mL, 48 wt % in H₂O). The reaction mixture was stirred at90-95° C. for 2 hours and then cooled to room temperature. The reactionmixture was diluted with EtOAc and washed with H₂O, saturated NaHCO₃,and saturated NaCl, dried over Na₂SO₄ and concentrated under reducedpressure. The crude product was triturated twice withdichloromethane/methanol and the resulting solid was collected and driedunder vacuum to yield 0.756 g (79%) pure desired product as a whitesolid.

Step E. Preparation of2-(4-bromo-2-fluorophenylamino)-6-oxo-1,6-dihydropyridine-3-carboxylicacid: To a suspension of2-(4-bromo-2-fluorophenylamino)-6-oxo-1,6-dihydropyridine-3-carboxylicacid methyl ester (0.050 g, 0.147 mmol) in methanol (1.5 mL) was added 1M NaOH (1.47 mL, 1.47 mmol). The reaction mixture was stirred at 75-80°C. for 2 days. The reaction mixture was diluted with H>0 and the pH wasadjusted with 1 M HCl until 1-2. The reaction mixture was diluted withEtOAc and washed with saturated NaCl, dried (Na₂SO₄), and concentratedunder reduced pressure. The crude product was triturated with diethylether/dichloromethane and the resulting solid was collected and driedunder vacuum to yield 0.033 g (69%) pure desired product as a yellowsolid. MS ESI (+) m/z 327, 329 (M+, Br pattern) detected; ¹H NMR (400mHz, DMSO-d₆) δ 13.1 (br s, 1H), 11.5 (s, 1H), 10.9 (s, 1H), 8.77 (br s,1H), 8.10 (d, 1H), 7.59 (d, 1H), 7.35 (d, 1H) 6.16 (m, 1H).

Example 163

2-(4-Bromo-2-fluorophenylamino)-6-oxo-1,6-dihydropyridine-3-carboxylicacid cyclopropylmethoxy-amide

2-(4-Bromo-2-fluorophenylamino)-6-oxo-1,6-dihydropyridine-3-carboxylicacid (0.025 g, 0.076 mmol) was converted to the desired productfollowing the procedure described in Example 154 to yield 0.023 g (76%)pure desired product as a pale yellow solid. MS ESI (+) m/z 396, 398(M+, Br pattern) detected; ¹H NMR (400 mHz, DMSO-d₆) δ 11.6 (s, 1H),11.3 (s, 1H), 11.2 (s, 1H), 9.74 (br s, 1H), 7.90 (d, 1H), 7.56 (d, 1H),7.32 (d, 1H), 6.13 (d, 1H) 3.70 (d, 2H) 1.10 (m, 1H), 0.54 (m, 2H), 0.27(m, 2H).

Example 164

4-(2-Fluoro-4-methylphenylamino)-1,3-dimethyl-7,8-dihydro-1H,6H-pyrido[2,3-d]pyridazine-2,5-dione

To a solution of2-bromomethyl-4-(2-fluoro-4-methylphenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid ethyl ester (1 equivalent) in MeOH is added hydrazine (1.10equivalents). After stirring for 2 hours at room temperature, thereaction mixture is heated to 40° C. for 8 hours. The reaction mixtureis diluted with EtOAc and washed with water. The organic layer is driedover MgSO₄, filtered, and concentrated in vacuo to give the crudematerial that is purified by trituration or flash column chromatographyto afford the desired product as necessary.

Example 165

4-(2-Fluoro-4-methylphenylamino)-1,3,8-trimethyl-1H,6H-pyrido[2,3-d]pyridazine-2,5-dione

Step A: Preparation of2-bromo-4-chloro-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid ethyl ester: To a solution of4-chloro-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid ethylester (1.00 equivalent) in DMF is added NBS (1.20 equivalents) at roomtemperature. After stirring for 16 hours at room temperature, thereaction mixture is diluted with EtOAc and washed with water. Theorganic layer is dried over MgSO₄, filtered, and concentrated in vacuoto give the crude material that is purified by trituration or Hashcolumn chromatography to afford the desired product as necessary.

Step B: Preparation of4-chloro-1,5-dimethyl-6-oxo-2-trimethylsilanylethynyl-1,6-dihydropyridine-3-carboxylicacid ethyl ester: To a mixture of2-bromo-4-chloro-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid ethyl ester (1.00 equivalent), trimethylsilylacetylene (1.20equivalents) and iPr₂NH (2.00 equivalents) in THF is added CuI (0.10equivalents) followed by Pd(PPh₃)₂Cl₂ (0.10 equivalents). After stirringthe reaction mixture at reflux for 16 hours, it is cooled to roomtemperature and diluted with ethyl acetate. The organic layer is washedwith saturated NH₄Cl solution and brine, dried (MgSO₄) and concentratedunder reduced pressure. The desired product is obtained by flash columnchromatography as necessary.

Step C: Preparation of2-acetyl-4-chloro-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid ethyl ester: A mixture of4-chloro-1,5-dimethyl-6-oxo-2-trimethylsilanylethynyl-1,6-dihydropyridine-3-carboxylicacid ethyl ester (1.00 equivalent), HgSO₄ (1.00 equivalent) and H₂SO₄(2.00 equivalents) in ˜6:1 acetone:water is refluxed for 3 hours. Thereaction mixture is cooled to room temperature and concentrated underreduced pressure. The residue is diluted with a mixture of THF and ethylacetate and washed with water and brine. The organic layer is dried(MgSO₄) and concentrated under reduced pressure. The desired product isobtained by Hash column chromatography as necessary.

Step D: Preparation of2-acetyl-4-chloro-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid: To a solution of2-acetyl-4-chloro-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid ethyl ester (1.00 equivalent) in THF:water (4:1) is added 1 Maqueous LiOH solution (2.05 equivalents). After 30 minutes, the reactionmixture is acidified to pH ˜1 with 1 N HCl solution and extracted withethyl acetate. The combined organic extracts are dried (MgSO₄) andconcentrated under reduced pressure to give the desired product which isused directly without further purification.

Step E: Preparation of4-chloro-1,3,8-trimethyl-1H,6H-pyrido[2,3-d]pyridazine-2,5-dione: To asolution of2-acetyl-4-chloro-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid (1 equivalent) and hydrazine monohydrate (3.30 equivalents) in THFis added 1 N HCl (0.80, equivalents). After 16 hours, the reactionmixture is diluted with ethyl acetate, washed with water and brine,dried (MgSO₄) and concentrated under reduced pressure. The desiredproduct purified by trituration or flash column chromatography to affordthe desired product as necessary.

Step F: Preparation of4-(2-fluoro-4-methylphenylamino)-1,3,8-trimethyl-1H,6H-pyrido[2,3-d]pyridazine-2,5-dione:2-Fluoro-4-methylphenylamine (1.10 equivalents), palladium (II) acetate(0.10 equivalents), rac-2,2-bis(diphenylphosphino)-1,1′-binaphthyl (0.15equivalents), and cesium carbonate (1.50 equivalents) are added to asolution of4-chloro-1,3,8-trimethyl-1H,6H-pyrido[2,3-d]pyridazine-2,5-dione (1.00equivalent) in toluene in a sealed vial. After stirring 10 minutes, themixture is heated to 80° C. After 24 hours, the reaction mixture iscooled to room temperature and diluted with EtOAc. The resultingprecipitate is filtered and washed with EtOAc. The filtrate is dilutedwith EtOAc and washed with water. The aqueous layer is reextracted withEtOAc. The combined organic layers are washed with brine, dried (Na₂SO₄)and concentrated. Purification by flash column chromatography gives thedesired product.

Example 166

4-(2-Fluoro-4-(methylthio)phenylamino)-N-(2-hydroxyethoxy)-1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxamide

Step A: Preparation of ethyl 2-(2-methylhydrazono)propanoate: To asuspension of ethyl pyruvate (37.8 mL, 338 mmol) and MgSO₄ (40.8 g, 339mmol) in CHCl₃ (500 mL) was added a solution of methylhydrazine (18.0mL, 332 mmol) in CHCl₃ (100 mL) at 0° C. The reaction mixture was warmedto room temperature. After stirring for 24 hours at room temperature,the reaction mixture was filtered. The filtrate was concentrated underreduced pressure to give 44 g (94%) of the desired product that was useddirectly without further purification.

Step B: Preparation of methyl3-(2-(1-ethoxy-1-oxopropan-2-ylidene)-1-methylhydrazinyl)-3-oxopropanoate:To a solution of ethyl 2-(2-methylhydrazono)propanoate (25.0 mL, 186mmol) in THF (500 mL) al 0° C. was added LiH (2.02 g, 241 mmol). Theresulting mixture was stirred for 10 minutes at 0° C., warmed to roomtemperature, and stirred for 6 hours. Methyl malonyl chloride (26.7 mL,242 mmol) in THF (20 mL) was added at 0° C. The reaction was warmed toroom temperature and stirred for 16 hours. The reaction was carefullyquenched with 1N aqueous HCl at 0° C., concentrated under reducedpressure, and diluted with EtOAc. The organic layer was dried overMgSO₄, filtered, and concentrated under reduced pressure to give 46 g(99%) of the desired product that was used directly without furtherpurification,

Step C: Preparation of methyl5-hydroxy-2,6-dimethyl-3-oxo-2,3-dihydropyridazine-4-carboxylate: To asolution of ethyl 2-(2-methyl-2-(methyl3-oxopropanoyl)hydrazono)propanoate (1.02 g, 4.09 mmol) in MeCN (10 mL)at 0° C. was added DBU (2.0 mL, 13 mmol). The reaction mixture waswarmed to room temperature and stirred for 3 hours. The reaction mixturewas concentrated under reduced pressure and diluted with EtOAc. Theorganic layer was washed with 10% aqueous HCl, dried over MgSO₄,filtered, and concentrated under reduced pressure to give 0.39 g (48%)of the crude product that was used directly without furtherpurification.

Step D: Preparation of 5-hydroxy-2,6-dimethylpyridazin-3(2H)-one: Amixture of methyl5-hydroxy-2,6-dimethyl-3-oxo-2,3-dihydropyridazine-4-carboxylate (3.00g, 15.1 mmol) and 6 N aqueous HCl (25 mL, 150 mmol) in dioxane (25 mL)was refluxed for 48 hours. The reaction mixture was cooled to roomtemperature and concentrated under reduced pressure to give the crudematerial that was diluted with EtOAc. The organic layer was washed withwater and brine, dried over MgSO₄, filtered, and concentrated underreduced pressure to give 0.74 g (35%) of the desired product. Theaqueous layer was concentrated under reduced pressure. The resultingsolid was diluted with water and EtOAc-THF. The organic layer wasseparated. The aqueous layer was extracted with EtOAc (2×). The combinedorganic layers were dried over MgSO₄, filtered, and concentrated underreduced pressure to give 0.80 g (37%) of the additional desired product.A total of 1.54 g (72%) of the desired product was obtained, which wasused directly without further purification.

Step E: Preparation of 5-chloro-2,6-dimethylpyridazin-3(2H)-one: Amixture of 5-hydroxy-2,6-dimethylpyridazin-3(2H)-one (736 mg, 5.25 mmol)and POCl₃ (4.5 mL) was stirred at 85° C. for 2 hours. The reactionmixture was concentrated under reduced pressure to give the crudematerial that was quenched with saturated aqueous Na₂CO₃. The resultingmixture was stirred for 2 hours and extracted with EtOAc (3×). Thecombined organic layers were dried over MgSO₄, filtered, andconcentrated under reduced pressure to give 587 mg (70%) of the desiredproduct that was used directly without further purification.

Step F: Preparation of4-chloro-1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxylic acid: To asolution of 5-chloro-2,6-dimethylpyridazin-3(2H)-one (780 mg, 4.67 mmol)in fuming H₂SO₄ (25 mL) at 0° C. was slowly, added K₂Cr₂O₇ (3.33 g, 11.2mmol) with stirring. After the addition of K₂Cr₂O₇, the ice-bath wasremoved and the reaction mixture was allowed to warm to roomtemperature. When the reaction began to progress too rapidly, theice-bath was replaced and the rest of k₂Cr₂O₇ was added. The reactionmixture was stirred al 60° C. for 16 hours. The reaction mixture wascooled to room temperature, poured into ice, and extracted with EtOAc(3×). The combined organic layers were dried over MgSO₄, filtered, andconcentrated under reduced pressure to give 649 mg (74%) of the desiredproduct that was used directly without further purification.

Step G: Preparation of methyl4-chloro-1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxylate: A solutionof 4-chloro-1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxylic acid (390mg, 2.07 mmol) and cone. HCl (0.10 mL) in MeOH (6 mL) was refluxed for 8hours. The reaction mixture was cooled to room temperature andconcentrated under reduced pressure to give the crude material that wasredissolved into EtOAc. The organic layer was washed with water, driedover MgSO₄, filtered, and concentrated under reduced pressure to givethe crude material that was purified by silica gel flash columnchromatography (100% hexanes to 10 to 20 to 30 to 50% EtOAc in hexanes)to afford 72 mg (17%) of the desired product.

Step H: Preparation of methyl4-(2-fluoro-4-(methylthio)phenylamino)-1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxylate:A mixture solution of methyl4-chloro-1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxylate (72 mg, 0.35mmol), 2-fluoro-4-methylthioaniline (69 mg, 0.44 mmol), Pd(OAc)₂ (10 mg,0.044 mmol). BINAP (40 mg. 0.064 mmol), and Cs₂CO₃ (197 mg, 0.60 mmol)in toluene (1.5 mL) was sealed in a vial under N₂ atmosphere. It wasstirred for 10 minutes at room temperature and then heated al 80° C. for16 hours with stirring. The reaction mixture was cooled to roomtemperature and diluted with EtOAc. The precipitate was filtered off andwashed with EtOAc. The filtrate was washed with water. The organic layerwas separated and the aqueous layer was extracted with EtOAc. Thecombined organic layers were dried over MgSO₄, filtered, concentrated togive the crude material that was purified by silica gel flash columnchromatography (100% CH₂Cl₂ to 1% MeOH in CH₂Cl₂) followed by additionalsilica gel flash column chromatography (10 to 15 to 20% EtOAc in CH₂Cl₂)to afford 48 mg (42%) of the desired product.

Step I: Preparation of4-(2-fluoro-4-(methylthio)phenylamino)-1-methyl-6-oxo-N-(2-(vinyloxy)ethoxy)-1,6-dihydropyridazine-3-carboxamide:To a solution of methyl4-(2-fluoro-4-(methylthio)phenylamino)-1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxylate(25 mg, 0.077 mmol) and O-(2-vinyloxy-ethyl)-hydroxylamine (24 mg, 0.23mmol) in THF (2 mL) at 0° C. was added LiHMDS (0.54 mL, 0.54 mmol, 1 Min THF). The reaction mixture was warmed to room temperature and stirredfor 1 hour. The reaction mixture was quenched with saturated aqueousNaHCO₃ and diluted with EtOAc. The organic layer was washed with brine,dried over MgSO₄, filtered, and concentrated under reduced pressure togive the crude material that was purified by silica gel flash columnchromatography (100% CH₂Cl₂ to 1.5% MeOH in CH₂Cl₂) to afford 30 mg(99%) of the desired product.

Step J:. Preparation of4-(2-fluoro-4-(methylthio)phenylamino)-N-(2-hydroxyethoxy)-1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxamide:To a solution of4-(2-fluoro-4-(methylthio)phenylamino)-1-methyl-6-oxo-N-(2-(vinyloxy)ethoxy)-1,6-dihydropyridazine-3-carboxamide(30 mg, 0.077 mmol) in EtOH/THF (2 mL/2 mL) was added 1 N aqueous HCl(0.15 mL, 0.15 mmol, 1 N aqueous solution) at room temperature. Thereaction mixture was stirred for 1 hour at room temperature. Thereaction mixture was neutralized to pH 7, diluted with EtOAc (3×),washed with water, dried over MgSO₄, filtered, and concentrated underreduced pressure to give the crude material that was purified by silicagel flash column chromatography (100% EtOAc to 100% CH₂Cl₂ to 2.5 to 3to 5% MeOH in CH₂Cl₂) to afford 6 mg (22%) of the desired product. MSAPCI (−) m/z 367 (M−1) detected;

¹H NMR (400 MHz, CD₃OD) δ 7.35 (t, 1H), 7.18 (dd, 1H), 7.14 (dd, 1H),5.92 (s, 1H), 4.06 (t, 2H), 3.79 (t, 2H), 3.74 (s, 3H), 2.51 (s, 3H).

Example 167

5-Bromo-4-<4-bromo-2-fluorophenylamino)-N-(cyclopropylmethoxy)-1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxamide

Step A: Preparation of methyl4-(2-fluorophenylamino)-1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxylate:The title compound was prepared in 61% yield by the procedure aspreviously described in Example 166 (step H) using methyl4-chloro-1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxylate (109 mg,0.54 mmol, prepared as previously described in Example 1 (steps A-G) and2-fluoroaniline (0.053 mL, 0.54 mmol).

Step B: Preparation of methyl5-bromo-4-(4-bromo-2-fluorophenylamino)-1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxylate:A mixture of methyl4-(2-fluorophenylamino)-1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxylate(88 mg, 0.32 mmol) and NBS (59 mg, 0.33 mmol) in DMF (1.5 mL) wasstirred for 2 hours at room temperature. The reaction mixture wasdiluted with EtOAc and washed with water (2×). The organic layer wasdried over MgSO₄, filtered, and concentrated under reduced pressure togive the crude material that was purified by silica gel flash columnchromatography (100% CH₂Cl₂ to 0.5% MeOH in CH₂Cl₂) followed byadditional silica gel flash column chromatography (30% EtOAc in CH₂Cl₂)to give 80 mg of a mixture of methyl5-bromo-4-(2-fluorophenylamino)-1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxylateand methyl5-bromo-4-(4-bromo-2-fluorophenylamino)-1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxylate.This mixture was re-submitted for bromination. To this mixture was addedDMF (1.5 mL) followed by NBS (29 mg, 0.22 mmol) at room temperature. Thereaction mixture was stirred for 2.5 hours at room temperature.Additional 15 mg of NBS was added and the reaction mixture was stirredfor additional 20 hours at room temperature. The reaction mixture wasdiluted with EtOAc and washed with water (2×). The organic layer wasdried over MgSO₄, filtered, and concentrated under reduced pressure togive the crude material that was purified by silica gel flash columnchromatography (30% EtOAc in CH₂Cl₂) to afford 62 mg (64%) of thedesired product.

Step C: Preparation of5-bromo-4-(4-bromo-2-fluorophenylamino)-N-(cyclopropylmethoxy)-1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxamide:The title compound was prepared in 40% yield by the procedure describedin Example 166 (step I) using methyl5-bromo-4-(4-bromo-2-fluorophenylamino)-1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxylate(31 mg, 0.071 mmol) and O-cyclopropylmethyl-hydroxylamine (20 mg, 0.23mmol). MS APCI (−) m/z 487, 489, 491 (M−1. Br pattern) detected; ¹H NMR(400 MHz, CD₃OD) δ 7.38 (dd, 1H), 7.31 (dd, 1H), 7.05 (t, 1H), 3.82 (s,3H), 3.65 (d, 2H), 1.13 (m, 1H), 0.58 (q, 2H), 0.31 (q, 2H).

Example 168

4-(2-fluoro-4-(methylthio)phenylamino)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridazine-3-carboxamide

Step A: Preparation of N-methylpropionohydrazide: To a solution ofmethylhydrazine (27.6 mL, 508 mmol) and catalytic amount of DMAP inCH₂Cl₂ (130 mL) at 0° C. was added a solution of acetylchloride (15.0mL, 169 mmol) in CH₂Cl₂ (30 mL). The reaction mixture was warmed to roomtemperature and stirred for 16 hours. The white solids were filtered offand the filtrate was concentrated under reduced pressure to give thecrude material that was purified by vacuum distillation to afford 8.25 g(48%) of the desired product (63-66° C. at 0.14 mm Hg).

Step B: Preparation of diethyl2-(2-methyl-2-propionylhydrazono)malonate: A solution ofN-methylpropionohydrazide (18.78 g, 183.9 mmol) and diethyl ketomalonate(56.1 mL, 368 mmol) in toluene (136 mL) was refluxed with a Dean-Starktrap for 4 hours. The reaction mixture was concentrated under reducedpressure to give the crude material that was purified by silica gelflash column chromatography (100% hexanes to 5 to 10% EtOAc in hexanes)to afford 23 g (49%) of the desired product.

Step C: Preparation of ethyl4-hydroxy-1,5-dimethyl-6-oxo-1,6-dihydropyridazine-3-carboxylate: To asolution of LiHMDS (0.78 mL, 0.78 mmol, 1 M solution in THF) in THF (1mL) at −78° C. was added a solution of diethyl2-(2-methyl-2-propionylhydrazono)malonate (50 mg, 0.19 mmol) in THF (1mL). The resulting mixture was slowly warmed to −40° C. and stirred for1.5 hours al −40° C. The reaction mixture was quenched with 10% aqueousHCl and diluted with water. The resulting mixture was extracted withEtOAc (2×). The combined organic layers were washed with water, driedover MgSO₄, filtered, and concentrated under reduced pressure to givethe crude material that was purified by silica gel flash columnchromatography (100% hexanes to 20% EtOAc in hexanes) to afford 25 mg(61%) of the desired product.

Step D: Preparation of ethyl4-chloro-1,5-dimethyl-6-oxo-1,6-dihydropyridazine-3-carboxylate: Amixture of ethyl4-hydroxy-1,5-dimethyl-6-oxo-1,6-dihydropyridazine-3-carboxylate (1.85g, 8.72 mmol) and POCl₃ (9 mL) was heated for 16 hours at 85° C. POCl₃was removed under reduced pressure. Then the crude material was quenchedwith ice-water. The mixture was neutralized with saturated aqueousNaHCO₃ (pH ˜6 to 7) and extracted with EtOAc (3×). The combined organiclayers were dried over MgSO₄, filtered, and concentrated under reducedpressure to give the crude material that was purified by silica gelflash column chromatography (100% hexanes to 5 to 10 to 20% EtOAc inhexanes) to afford 1.72 g (86%) of the desired product.

Step E: Preparation of ethyl4-(2-fluoro-4-(methylthio)phenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridazine-3-carboxylate:The title compound was prepared in 81% yield by the procedure describedin Example 166 (step H) using ethyl4-chloro-1,5-dimethyl-6-oxo-1,6-dihydropyridazine-3-carboxylat (500 mg,2.17 mmol) and 2-fluoro-4-methylthioaniline (375 mg, 2.38 mmol).

Step F: Preparation of4-(2-fluoro-4-(methylthio)phenylamino)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridazine-3-carboxamide:The title compound was prepared in 78% yield (2 steps) by the proceduresdescribed in Example 166 (steps I and J) using ethyl4-(2-fluoro-4-(methylthio)phenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridazine-3-carboxylate(50 mg, 0.14 mmol) and O-(2-vinyloxy-ethyl)-hydroxylamine (44 mg, 0.43mmol). MS APCI (−) m/z 381 (M−1) detected: ¹H NMR (400 MHz, CD₃OD) δ7.10 (dd, 1H), 7.03 (dd, 1H), 6.87 (t, 1H), 3.99 (t, 2H), 3.79 (s, 3H),3.74 (t, 2H), 2.47 (s, 3H), 1.74 (s, 3H).

The following compounds were prepared by the procedure as described inExample 166 (step I) using ethyl4-(2-fluoro-4-(methylthio)phenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridazine-3-carboxylateand the appropriate hydroxylamine.

Example 169

N-(Cyclopropylmethoxy)-4-(2-fluoro-4-(methylthio)phenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridazine-3-carboxamide

MS APCI (−) m/z 391 (M−1) detected; ¹H NMR (400 MHz. CD₃OD) δ 7.09 (dd,1H), 7.03 (dd, 1H), 6.86 (t, 1H), 3.78 (s, 3H), 3.71 (d, 2H), 2.47 (s,3H), 1.75 (s, 3H) 1.16 (m, 1H), 0.58 (m, 2H), 0.31 (m, 2H).

Example 170

4-(2-Fluoro-4-(methylthio)phenylamino)-N-(2-methoxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridazine-3-carboxamide

MS APCI (−) m/z 395 (M−1) detected; ¹H NMR (400 MHz, CD₃OD) δ 7.10 (dd,1H), 7.03 (d, 1H), 6.87 (t, 1H), 4.05 (t, 2H), 3.78 (s, 3H), 3.64 (t,2H), 3.37 (s, 3H); 2.47 (s, 3H), 1.74 (s, 3H).

Example 171

4-(2-Fluoro-4-(methylthio)phenylamino)-N-methoxy-1,5-dimethyl-6-oxo-1,6-dihydropyridazine-3-carboxamide

MS APCI (−) m/z 351 (M−1) detected; ¹H NMR (400 MHz, CD₃OD) 7.10 (d,1H), 7.04 (d, 1H), 6.87 (t, 1H), 3.78 (s, 3H), 3.76 (s, 3H), 2.47 (s,3H), 1.74 (s, 3H).

Example 172

4-(2-Fluoro-4-iodophenylamino)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridazine-3-carboxamide

Step A: Preparation of4-hydroxy-1,5-dimethyl-6-oxo-1,6-dihydropyridazine-3-carboxylic acid: Toa solution of LiHMDS (331 mL, 331 mmol, 1 M solution in THF) in THF (430mL) at −78° C. was added a solution of diethyl2-(2-methyl-2-propionylhydrazono)malonate (21.40 g, 82.86 mmol) preparedby the procedure described in Example 168 (step B) in THF (10 mL). Theresulting mixture was slowly warmed to −40° C. over 1 hour and stirredfor 1.5 hours at −40° C. To the −40° C. reaction mixture was added water(500 mL). The reaction mixture was warmed to room temperature andstirred for 3 hours. The reaction mixture was concentrated under reducedpressure to remove the THF. The resulting aqueous mixture was quenchedwith 6 N aqueous HCl at 0° C. and acidified to pH 1 to 2. The resultingmixture was stirred for 16 hours at room temperature. The precipitateswere filtered off and triturated with CH₂Cl₂ to afford 7.21 g (47%) ofthe desired product. The filtrate was extracted with EtOAc (3×). Thecombined organic layers were washed with water, dried over MgSO₄,filtered, and concentrated under reduced pressure to give the crudematerial that was triturated with CH₂Cl₂ to afford 3.56 g (23%) ofadditional desired product. The aqueous layer was extracted again withEtOAc (3×). The combined organic layers were washed with water, driedover MgSO₄, filtered, and concentrated under reduced pressure to givethe crude material that was triturated with CH₂Cl₂ to afford 1.32 g (9%)of additional desired product. A total of 12.09 g (79%) of the desiredproduct was obtained.

Step B: Preparation of4-chloro-1,5-dimethyl-6-oxo-1,6-dihydropyridazine-3-carboxylic acid: Amixture of4-hydroxy-1,5-dimethyl-6-oxo-1,6-dihydropyridazine-3-carboxylic acid(876 mg, 4.76 mmol) and POCl₃ (4.5 mL) was healed for 24 hours at 85° C.POCl₃ was removed under reduced pressure. The crude material wasquenched with ice. The reaction mixture was stirred for 1 hour at roomtemperature. After removing solids by filtration, the aqueous filtratewas extracted with EtOAc (3×). The combined organic layers were driedover MgSO₄, filtered, and concentrated under reduced pressure to give.The recovered material was combined with the solids previously isolatedand triturated with ether to afford 577 mg (60%) of the desired product.

Step C: Preparation of4-(2-fluoro-4-iodophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridazine-3-carboxylicacid: To a suspension of4-chloro-1,5-dimethyl-6-oxo-1,6-dihydropyridazine-3-carboxylic acid (200mg, 0.99 mmol) and 2-fluoro-4-indoaniline (478 mg, 1.97 mmol) in THF(6.5 mL) at −78° C. was slowly added a solution of LiHMDS (3.00 mL, 3.00mmol, 1 M solution in THF). After complete addition, the resultingmixture was slowly warmed to room temperature and stirred for 4 hours.The reaction mixture was quenched with 6 N aqueous HCl (8 mL) at 0° C.,warmed to room temperature, and stirred for 1.5 hours. The precipitateswere filtered, washed with water and ether, and triturated with ether toafford 158 mg (38%) of the desired product.

Step D: Preparation of4-(2-fluoro-4-iodophenylamino)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridazine-3-carboxamide:To a suspension of4-(2-fluoro-4-iodophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridazine-3-carboxylicacid (41 mg, 0.10 mmol) and HOBt (28 mg, 0.21 mmol) in DMF (1.5 mL) wasadded EDCl (40 mg, 0.21 mmol) al room temperature. The resulting mixturewas stirred for 1.5 hours. O-(2-Vinyloxy-ethyl)-hydroxylamine (21 mg,0.20 mmol) and TEA (0.030 mL, 0.22 mmol) was added to the activatedester at room temperature. After stirring for 1.5 hours, the reactionmixture was diluted with EtOAc and washed with saturated aqueous NH₄Cl,brine, saturated aqueous NaHCO₃ (2×), and brine. The organic layer wasseparated, dried over MgSO₄, filtered, and concentrated under reducedpressure to give4-(2-fluoro-4-iodophenylamino)-1,5-dimethyl-6-oxo-N-(2-(vinyloxy)ethoxy)-1,6-dihydropyridazine-3-carboxamidethat was used directly without further purification. The title compoundwas prepared by the procedure previously described in Example 1 (step J)using the crude4-(2-fluoro-4-iodophenylamino)-1,5-dimethyl-6-oxo-N-(2-(vinyloxy)ethoxy)-1,6-dihydropyridazine-3-carboxamide(40% yield over two steps). MS APCI (−) m/z 461 (M−1) detected; ¹H NMR(400 MHz, CD₃OD) δ 7.52 (dd, 1H), 7.44 (d, 1H), 6.63 (t, 1H), 3.98 (t,2H), 3.80 (s, 3H), 3.74 (t, 2H), 1.78 (s, 3H).

The following compounds were prepared by the procedures as previouslydescribed in Example 172 (steps C and D) using the appropriate anilinesand hydroxylamine. In some instances, a final deprotection step may berequired. These deprotections can be accomplished by standard literaturemethods

Example 173

(R)—N-(2,3-Dihydroxypropoxy)-4-(2-fluoro-4-iodophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridazine-3-carboxamide

MS APCI (−) m/z 491 (M−1) detected; ¹H NMR (400 MHz. CD₃OD) δ 7.52 (dd,1H), 7.44 (d, 1H), 6.63 (t, 1H), 4.02 (m, 1H), 3.88 (m, 2H), 3.80 (s,3H), 3.59 (m, 2H), 1.77 (s, 3H).

Example 174

4-(2-Fluoro-4-iodophenylamino)-N-methoxy-1,5-dimethyl-6-oxo-1,6-dihydropyridazine-3-carboxamide

MS APCI (−) m/z 431 (M−1) detected; ¹H NMR (400 MHz, CD₃OD) δ 7.52 (dd,1H), 7.44 (d, 1H), 6.63 (t, 1H), 3.79 (s, 3H), 3.75 (s, 3H), 1.77 (s,3H).

Example 175

N-(Cyclopropylmethoxy)-4-(2-fluoro-4-iodophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridazine-3-carboxamide

MS APCI (−) m/z 471 (M−1) detected: ¹H NMR (400 MHz. CD₃OD) δ 7.51 (dd,1H), 7.44 (d, 1H), 6.62 (t, 1H), 3.79 (s, 3H), 3.70 (d, 2H), 1.78 (s,3H), 1.15 (m, 1H), 0.57 (q, 2H), 0.30 (q, 2H).

Example 176

4-(4-Bromo-2-fluorophenylamino)-N-(2-hydroxyethoxy)-1,5-<dimethyl-6-oxo-1,6-dihydropyridazine-3-carboxamide

MS APCI (−) m/z 413, 415 (M−1, Br pattern) detected; ¹H NMR (400 MHz,CD₃OD) δ 7.38 (dd, 1H), 7.27 (d, 1H), 6.79 (t, 1H), 3.99 (t, 2H), 3.80(s, 3H), 3.74 (t, 2H), 1.77 (s, 3H).

Example 177

(S)-4-(4-Bromo-2-fluorophenylamino)-N-(2-hydroxypropoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridazine-3-carboxamide

MS APCI (−) m/z 427, 429 (M−1, Br pattern) detected; ¹H NMR (400 MHz,CD₃OD) δ 7.39 (dd, 1H), 7.27 (dd, 1H), 6.79 (t, 1H), 3.98 (m, 1H), 3.84(dd, 1H), 3.80 (s, 3H), 3.72 (dd, 1H), 1.78 (s, 3H), 1.15 (d, 3H).

Example 178

Methyl2-(4-bromo-2-fluorophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylate

Step A. Preparation of 2-chloro-6-oxo-1,6-dihydro-pyridine-3-carboxylicacid: 2-Chloro-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid was preparedfrom dichloro-nicotinic acid (3.00 g, 15.6 mmol. Aldrich) according tothe procedure described in U.S. Pat. No. 3,682,932 to yield 1.31 g (48%)of the desired product.

Step B. Preparation of2-chloro-1-methyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid methylester: To a solution of 2-chloro-6-oxo-1,6-dihydro-pyridine-3-carboxylicacid (0.644 g, 3.71 mmol) in DMF (20 mL) was added lithium hydride (95%,0.078 g, 9.28 mmol) and the reaction mixture was stirred for 40 minutesunder N₂. Methyl iodide (0.508 mL, 1.16 g, 8.16 mmol) was then added andthe reaction mixture was stirred for an additional 45 minutes. Thereaction mixture was quenched with 2 M HCl until the pH was 6-7. Thereaction mixture was diluted with EtOAc and saturated NaCl and thelayers separated. The aqueous layer was back extracted with EtOAc (1×).The combined organic layers were dried (Na₂SO₄) and concentrated underreduced pressure to yield a crude yellow solid. HPLC analysis showed twoproducts in a 4:1 ratio that were separated by flash columnchromatography (methylene chloride/EtOAc, 15:1 to 10:1) to give 0.466 g(62%) pure desired product as a white crystalline solid. The minorproduct was also isolated as a pale yellow crystalline solid andidentified as the regioisomer 2-chloro-6-methoxy-nicotinic acid methylester.

Step C. Preparation of methyl5-bromo-2-chloro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate: To asolution of methyl2-chloro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate (0.100 g,0.496 mmol) in DMF (5 mL) was added N-bromosuccinimide (0.177 g, 0.992mmol) and the reaction mixture was stirred for 4 hours at roomtemperature under N₂. The reaction mixture was quenched with saturatedsodium bisulfite and then diluted with EtOAc and H₂O and the layersseparated. The aqueous layer was back extracted with EtOAc (2×). Thecombined organic layers were dried (Na₂SO₄) and concentrated underreduced pressure to yield a yellow solid in quantitative yield.

Step D. Preparation of methyl2-chloro-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylate: To asuspension of methyl5-bromo-2-chloro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate (0.400g, 1.43 mmol) and1,1′-bis(diphenylphosphino)ferrocenedichloropalladium(II) (0.0587 g,0.0713 mmol) in dioxane (8 mL) at 0° C. under N₂ was added dimethylzinc(0.713 mL, 1.43 mmol, 2 M solution in toluene). The reaction mixture wasimmediately heated to 100° C. for 30 minutes. The reaction mixture wascooled to 0° C. and quenched with MeOH (0.800 mL). The reaction mixturewas diluted with EtOAc and washed with 1 M HCl. The aqueous layer wasback extracted with EtOAc (1×). The combined organic layers were washedwith saturated NaCl, dried (Na₂SO₄) and concentrated under reducedpressure to a dark yellow gum. Purification by flash columnchromatography (methylene chloride/EtOAc, 15:1) gave 0.164 g (53%) puredesired product as a yellow crystalline solid.

Step E: Preparation of methyl2-(4-bromo-2-fluorophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylate:To a solution of 4-bromo-2-fluorobenzenamine (0.058 g, 0.31 mmol) in THF(2 mL) at −78° C. under N₂ was added lithium bis(trimethylsilyl)amide(0.56 mL, 0.56 mmol, 1 M solution in hexanes) dropwise. The reactionmixture was stirred for one hour at −78° C. Methyl2-chloro-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylate (0.060 g,0.28 mmol) was then added dropwise as a solution in THF (1 mL) and thereaction mixture was stirred for 25 minutes at −78° C. The reactionmixture was quenched by the addition of H₂O and the pH was adjusted with0.1M HCl and then diluted with EtOAc and saturated NaCl and the layersseparated. The aqueous layer was back extracted with EtOAc (1×). Thecombined EtOAc layers were dried (Na₂SO₄) and concentrated under reducedpressure. Purification by flash column chromatography (methylenechloride/EtOAc, 20:1) gave 0.086 g (84%) pure desired product as a whitecrystalline solid. MS ESI (+) m/z 371, 373 (M+, Br pattern) detected; ¹HNMR (400 MHz. CDCl₃) δ 9.57 (s, 1H), 7.79 (s, 1H), 7.32 (d, 1H), 7.18(d, 1H), 6.58 (t, 1H), 3.85 (s, 3H), 3.29 (s, 3H), 2.14 (s, 3H).

Example 179

2-(4-Bromo-2-fluorophenylamino)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide

Step A. Preparation of2-(4-bromo-2-fluorophenylamino)-1,5-dimethyl-6-oxo-N-(2-(vinyloxy)ethoxy)-1,6-dihydropyridine-3-carboxamide:To a solution of methyl2-(4-bromo-2-fluorophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylate(0.060 g, 0.16 mmol) in THF (2 mL) was addedO-(2-vinyloxy-ethyl)-hydroxylamine (0.042 ml, 0.41 mmol). The solutionwas cooled to 0° C. and lithium bis(trimethylsilyl)amide (0.81 ml, 0.81mmol, 1 M solution in hexanes) was added dropwise. The reaction mixturewas warmed to room temperature. After stirring for 35 minutes thereaction mixture was quenched by the addition of saturated NaHCO₃ andpartitioned between EtOAc and saturated NaCl. The layers were separatedand the organic layer was dried (Na₂SO₄) and concentrated under reducedpressure. Purification by Hash column chromatography (methylenechloride/MeOH, 20:1) gave 0.067 g (94%) pure desired product as anoff-white crystalline solid.

Step B. Preparation of2-(4-bromo-2-fluorophenylamino)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide:To a solution of2-(4-bromo-2-fluorophenylamino)-1,5-dimethyl-6-oxo-N-(2-(vinyloxy)ethoxy)-1,6-dihydropyridine-3-carboxamide(0.067 g, 0.150 mmol) in ethanol (2 mL) was added aqueous 2 M HCl (0.380mL, 0.760 mmol). The reaction mixture was stirred for 16 hours at roomtemperature. The pH of the reaction mixture was adjusted with 1 M NaOH.The reaction mixture was diluted with EtOAc and H₂O. The organic layerwas separated and washed with saturated NaCl. The combined aqueouslayers were back extracted with EtOAc (1×). The combined organic layerswere dried (Na₂SO₄) and concentrated under reduced pressure to yield0.060 g (94%) pure desired product as an off-white crystalline solid. MSESI (+) m/z 414, 416 (M+, Br pattern detected); ¹H NMR (400 MHz, CDCl₃)δ 9.80 (s, 1H), 8.44 (s, 1H), 7.31 (d, 1H), 7.19 (d, 1H), 6.59 (t, 1H),4.05 (m, 2H), 3.85 (m, 1H), 3.75 (m, 2H), 3.29 (s, 3H), 2.15 (s, 3H).

The following compounds were prepared using the methods as described inExamples 178 and 179. In some instances, such as Example 179, a finaldeprotection step may be required. These deprotections can beaccomplished by standard literature methods.

Example 180

Methyl2-(2-fluoro-4-iodophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylate

Methyl 2-chloro-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylate wasconverted to methyl2-(2-fluoro-4-iodophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylatefollowing the procedure described in Step E of Example 178 using2-fluoro-4-iodobenzenamine to yield the desired product as a whitecrystalline solid. MS ESI (+) m/z 417 (M+1) detected; ¹H NMR (400 MHz,CDCl₃) δ 9.56 (s, 1H), 7.79 (s, 1H), 7.49 (d, 1H), 7.36 (d, 1H), 6.43(t, 1H), 3.85 (s, 3H), 3.30 (s, 3H), 2.15 (s, 3H).

Example 181

2-(2-fluoro-4-iodophenylamino)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide

Methyl2-(2-fluoro-4-iodophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylatewas coupled and deprotected as described in Example 179 to yield thedesired product as a yellow solid. MS ESI (+) m/z 462 (M+1) patterndetected; ¹H NMR (400 MHz, CDCl₃) δ 9.77 (s, 1H), 8.50 (s, 1H), 7.47 (d,1H), 7.36 (d, 1H), 6.43 (t, 1H), 4.04 (br s, 2H), 3.85 (br s, 1H), 3.74(br s, 2H), 3.29 (s, 3H), 2.14 (s, 3H).

Example 182

(S)-2-(4-bromo-2-fluorophenylamino)-N-(2-hydroxypropoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide

Step A: Methyl2-(4-bromo-2-fluorophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylatewas converted to(S)-2-(4-bromo-2-fluorophenylamino)-N-(2-(tert-butyldimethylsilyloxy)propoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamidefollowing the procedure described in Step A of Example 179.

Step B: To a solution of(S)-2-(4-bromo-2-fluorophenylamino)-N-(2-(tert-butyldimethylsilyloxy)propoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide(0.037 g, 0.0682 mmol) in THF (1.00 mL) was added 1 M HCl (0.682 mL,0.682 mmol). The reaction mixture was stirred for one hour at roomtemperature. The reaction mixture was diluted with EtOAc and washed withsaturated NaHCO₃ (3×), saturated NaCl (1×), dried (Na₂SO₄) andconcentrated under reduced pressure. Purification by flash columnchromatography (methylene chloride/methanol, 30:1) gave 0.020 (69%) puredesired product as a yellow solid. MS ESI (+) m/z 428, 430 (M+, Brpattern) detected; ¹H NMR (400 MHz, CD₃OD) δ 7.55 (s, 1H), 7.40 (d, 1H),7.24 (d, 1H), 6.68 (t, 1H), 3.86 (m, 1H), 3.71 (m, 1H), 3.58 (m, 1H),3.40 (s, 3H), 2.12 (s, 3H), 1.10 (d, 3H).

Example 183

Methyl2-(4-bromo-2-fluorophenylamino)-5-ethyl-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate

Step A. Preparation of Methyl2-chloro-5-ethyl-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate:Methyl 5-bromo-2-chloro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylatewas converted to methyl2-chloro-5-ethyl-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate asdescribed in Step D of Example 178 using diethylzinc (1M in hexanes) toyield the desired product as a yellow crystalline solid.

Step B. Methyl2-(4-bromo-2-fluorophenylamino)-5-ethyl-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate:Methyl 2-chloro-5-ethyl-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylatewas converted to methyl2-(4-bromo-2-fluorophenylamino)-5-ethyl-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylateas described in Step E of Example 178. MS ESI (+) m/z 383, 385 (M+, Brpattern) detected; ¹H NMR (400 MHz, CDCl₃) δ 9.59 (s, 1H), 7.76 (s, 1H),7.32 (d, 1H), 7.18 (d, 1H), 6.59 (t, 1H), 3.86 (s, 3H), 3.28 (s, 3H),2.56 (q, 2H), 1.22 (t, 3H).

Example 184

2-(4-Bromo-2-fluorophenylamino)-5-ethyl-N-(2-hydroxyethoxy)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide

Methyl2-(4-bromo-2-fluorophenylamino)-5-ethyl-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylatewas coupled and deprotected as described in Example 179 to yield thedesired product as a yellow solid. MS APCI (+) m/z 428, 430 (M+, Brpattern) detected; ¹H NMR (400 MHz, DMSO-d₆) δ 11.51 (br s, 1H), 9.54(br s, 1H), 7.57 (d, 1H), 7.47 (s, 1H), 7.25 (d, 1H), 6.69 (t, 1H), 4.67(br s, 1H), 3.74 (m, 2H), 3.50 (m, 2H), 3.24 (s, 3H), 2.43 (q, 2H), 1.14(t, 3H).

Example 185

Methyl2-(4-bromo-2-fluorophenylamino)-5-chloro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate

Methyl2-(4-bromo-2-fluorophenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylatewas convened to methyl2-(4-bromo-2-fluorophenylamino)-5-chloro-1-methyl-oxo-1,6-dihydropyridine-3-carboxylateas described in Step A of Example 160 using N-chlorosuccinimide to yieldthe desired product as a white solid. MS ESI (+)m/z 389, 391, 393 (M+,Cl, Br pattern) detected; ¹H NMR (400 MHz, CDCl₃) δ 9.88 (s, 1H), 8.13(s, 1H), 7.34 (d, 1H), 7.24 (d, 1H), 6.69 (t, 1H), 3.87 (s, 3H), 3.29(s, 3H).

Example 186

2-(4-bromo-2-fluorophenylamino)-5-chloro-N-(2-hydroxyethoxy)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide

Methyl2-(4-bromo-2-fluorophenylamino)-5-chloro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylatewas coupled and deprotected as described in Example 179 to yield thedesired product as a pale yellow solid. MS APCI (+) m/z 434, 436, 438(M+, Cl, Br pattern) detected; ¹H NMR (400 MHz, DMSO-d₆) δ 11.56 (br s,1H), 9.75 (br s, 1H), 7.91 (s, 1H), 7.57 (d, 1H), 7.26 (d, 1H), 6.89 (t,1H), 4.68 (br s, 1H), 3.70 (m, 2H), 3.50 (m, 2H), 3.28 (s, 3H).

Example 187

Methyl5-cyano-2-(2-fluoro-4-(methylthio)phenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate

Step A: Preparation of methyl2-(2-fluoro-4-(methylthio)phenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate:Methyl2-(2-fluoro-4-(methylthio)phenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylatewas prepared from methyl2-chloro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate and2-fluoro-4-(methylthio)benzenamine as described in Step C of Example153.

Step B: Preparation of methyl5-bromo-2-(2-fluoro-4-(methylthio)phenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate:Methyl2-(2-fluoro-4-(methylthio)phenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylatewas converted to methyl5-bromo-2-(2-fluoro-4-(methylthio)phenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylateas described in Step A of Example 160.

Step C: Methyl5-cyano-2-(2-fluoro-4-(methylthio)phenylamino-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate:A mixture of methyl5-bromo-2-(2-fluoro-4-(methylthio)phenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate(0.020 g, 0.050 mmol), tris(dibenzylideneacetone)-dipalladium(0) (0.046g, 0.050 mmol), 1,1′-bis(diphenylphosphine)-ferrocene (0.055 g, 0.100mmol) and Zn(CN)₂ (0.006 g, 0.055 mmol) was heated at 120° C. for 2hours. The reaction mixture was diluted with EtOAc and H₂O and thelayers separated. The EtOAc layer was washed with saturated NH₄Cl andsaturated NaCl, dried (Na₂SO₄) and concentrated under reduced pressureto a dark yellow gum. Purification by flash column chromatography(methylene chloride/EtOAc, 10:1) gave 0.005 g (29%) pure desired productas a yellow solid. MS APCI (−) m/z 346 (M−1) detected; ¹H NMR (400 MHz,CDCl₃) δ 10.84 (s, 1H), 8.39 (s, 1H), 6.95-7.06 (m, 3H), 3.90 (s, 3H),3.17 (s, 3H), 2.50 (s, 3H).

Additional compounds of the present invention include compounds ofgeneral Formulas Ia as shown in Table 1.

TABLE 1 Ia

R⁷ R⁹ R¹ R⁸ R³ Me Me F Br H OH OMe OEt HOCH₂CH₂O HOCH₂C(Me)₂O(S)-MeCH(OH)CH₂O (R)-HOCH₂CH(OH)CH₂O c-PrCH₂O Me Me F I H OH OMe OEtHOCH₂CH₂O HOCH₂C(Me)₂O (S)-MeCH(OH)CH₂O (R)-HOCH₂CH(OH)CH₂O c-PrCH₂O MeMe F SMe H OH OMe OEt HOCH₂CH₂O HOCH₂C(Me)₂O (S)-MeCH(OH)CH₂O(R)-HOCH₂CH(OH)CH₂O c-PrCH₂O Me Me Cl Br H OH OMe OEt HOCH₂CH₂OHOCH₂C(Me)₂O (S)-MeCH(OH)CH₂O (R)-HOCH₂CH(OH)CH₂O c-PrCH₂O Me Me Cl I HOH OMe OEt HOCH₂CH₂O HOCH₂C(Me)₂O (S)-MeCH(OH)CH₂O (R)-HOCH₂CH(OH)CH₂Oc-PrCH₂O Me Me Cl SMe H OH OMe OEt HOCH₂CH₂O HOCH₂C(Me)₂O(S)-MeCH(OH)CH₂O (R)-HOCH₂CH(OH)CH₂O c-PrCH₂O Me F F Br H OH OMe OEtHOCH₂CH₂O HOCH₂C(Me)₂O (S)-MeCH(OH)CH₂O (R)-HOCH₂CH(OH)CH₂O c-PrCH₂O MeF F I H OH OMe OEt HOCH₂CH₂O HOCH₂C(Me)₂O (S)-MeCH(OH)CH₂O(R)-HOCH₂CH(OH)CH₂O c-PrCH₂O Me F F SMe H OH OMe OEt HOCH₂CH₂OHOCH₂C(Me)₂O (S)-MeCH(OH)CH₂O (R)-HOCH₂CH(OH)CH₂O c-PrCH₂O Me F Cl Br HOH OMe OEt HOCH₂CH₂O HOCH₂C(Me)₂O (S)-MeCH(OH)CH₂O (R)-HOCH₂CH(OH)CH₂Oc-PrCH₂O Me F Cl I H OH OMe OEt HOCH₂CH₂O HOCH₂C(Me)₂O (S)-MeCH(OH)CH₂O(R)-HOCH₂CH(OH)CH₂O c-PrCH₂O Me F Cl SMe H OH OMe OEt HOCH₂CH₂OHOCH₂C(Me)₂O (S)-MeCH(OH)CH₂O (R)-HOCH₂CH(OH)CH₂O c-PrCH₂O Me Cl F Br HOH OMe OEt HOCH₂CH₂O HOCH₂C(Me)₂O (S)-MeCH(OH)CH₂O (R)-HOCH₂CH(OH)CH₂Oc-PrCH₂O Me Cl F I H OH OMe OEt HOCH₂CH₂O HOCH₂C(Me)₂O (S)-MeCH(OH)CH₂O(R)-HOCH₂CH(OH)CH₂O c-PrCH₂O Me Cl F SMe H OH OMe OEt HOCH₂CH₂OHOCH₂C(Me)₂O (S)-MeCH(OH)CH₂O (R)-HOCH₂CH(OH)CH₂O c-PrCH₂O Me Cl Cl Br HOH OMe OEt HOCH₂CH₂O HOCH₂C(Me)₂O (S)-MeCH(OH)CH₂O (R)-HOCH₂CH(OH)CH₂Oc-PrCH₂O Me Cl Cl I H OH OMe OEt HOCH₂CH₂O HOCH₂C(Me)₂O (S)-MeCH(OH)CH₂O(R)-HOCH₂CH(OH)CH₂O c-PrCH₂O Me Cl Cl SMe H OH OMe OEt HOCH₂CH₂OHOCH₂C(Me)₂O (S)-MeCH(OH)CH₂O (R)-HOCH₂CH(OH)CH₂O c-PrCH₂O c-PrCH₂ Me FBr H OH OMe OEt HOCH₂CH₂O HOCH₂C(Me)₂O (S)-MeCH(OH)CH₂O(R)-HOCH₂CH(OH)CH₂O c-PrCH₂O c-PrCH₂ Me F I H OH OMe OEt HOCH₂CH₂OHOCH₂C(Me)₂O (S)-MeCH(OH)CH₂O (R)-HOCH₂CH(OH)CH₂O c-PrCH₂O c-PrCH₂ Me FSMe H OH OMe OEt HOCH₂CH₂O HOCH₂C(Me)₂O (S)-MeCH(OH)CH₂O(R)-HOCH₂CH(OH)CH₂O c-PrCH₂O c-PrCH₂ F F Br H OH OMe OEt HOCH₂CH₂OHOCH₂C(Me)₂O (S)-MeCH(OH)CH₂O (R)-HOCH₂CH(OH)CH₂O c-PrCH₂O c-PrCH₂ F F IH OH OMe OEt HOCH₂CH₂O HOCH₂C(Me)₂O (S)-MeCH(OH)CH₂O (R)-HOCH₂CH(OH)CH₂Oc-PrCH₂O c-PrCH₂ F F SMe H OH OMe OEt HOCH₂CH₂O HOCH₂C(Me)₂O(S)-MeCH(OH)CH₂O (R)-HOCH₂CH(OH)CH₂O c-PrCH₂O

Additional compounds of the present invention include compounds ofgeneral Formulas Va-Vg as shown in Tables 2-8.

TABLE 2 Va

R⁹ R³ Me

Et

Cl

TABLE 3 Vb

R⁹ R³ Me H

Et H

Cl H

TABLE 4 Vc

R⁹ R³ Me H

Et H

Cl H

TABLE 5 Vd

R⁹ R³ Me H

Et H

Cl H

TABLE 6 Ve

R⁹ R³ Me H

Et H

CN H

Cl H

TABLE 7 Vf

R⁹ R³ Me H

Et H

CN H

Cl H

TABLE 8 Vg

R⁹ R⁸ R¹ R³ Me I F H Me Cl H Me Br F H Me Cl H Me SMe F H Me Cl H Me EtI F H Me Cl H Me Br F H Me Cl H Me SMe F H Me Cl H Me CN SMe F H Me Cl HMe Cl I F H Me Cl H Me Br F H Me Cl H Me SMe F H Me Cl H Me

The foregoing description is considered as illustrative only of theprinciples of the invention. Further, since numerous modifications andchanges will be readily apparent to those skilled in the art, it is notdesired to limit the invention to the exact construction and processshown as described above. Accordingly, all suitable modifications andequivalents may be resorted to falling within the scope of the inventionas defined by the claims that follow.

The words “comprise,” “comprising,” “include,” “including,” and“includes” when used in this specification and in the following claimsare intended to specify the presence of stated features, integers,components, or steps, but they do not preclude the presence or additionof one or more other features, integers, components, steps, or groupsthereof.

1. A compound including tautomers, resolved enantiomers, diastereomers,and pharmaceutically acceptable salts thereof, said compound having theformula:

wherein R¹, R², and R⁹ are independently hydrogen, halogen, cyano,nitro, trifluoromethyl, difluoromethyl, fluoromethyl, fluoromethoxy,difluoromethoxy, trifluoromethoxy, azido, —SR¹¹, —OR³, —C(O)R³,—C(O)OR³, —NR⁴C(O)OR⁶, —OC(O)R³, —NR⁴SO₂R⁶, —SO₂NR³R⁴, —NR⁴C(O)R³,—C(O)NR³R⁴, —NR⁵C(O)NR³R⁴, —NR⁵C(NCN)NR³R⁴, —NR³R⁴, C₁-C₁₀ alkyl, C₂-C₁₀alkenyl, C₂-C₁₀alkynyl, C₃-C₁₀ cycloalkyl, C₄-C₁₀ cycloalkylalkyl,—S(O)_(j)(C₁-C₆ alkyl), —S(O)_(j)(CR⁴R⁵)_(m)-aryl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl,—O(CR⁴R⁵)_(m)-aryl, —NR⁴(CR⁴R⁵)_(m)-aryl, —O(CR⁴R⁵)_(m)-heteroaryl,—NR⁴(CR⁴R⁵)_(m)-heteroaryl, —O(CR⁴R⁵)_(m)-heterocyclyl or—NR⁴(CR⁴R⁵)_(m)-heterocyclyl, wherein any of said alkyl, alkenyl,alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,heterocyclyl and heterocyclylalkyl portions are optionally substitutedindependently with one or more groups independently selected from oxo(with the proviso that it is not substituted on an aryl or heteroaryl),halogen, cyano, nitro, trifluoromethyl, difluoromethoxy,trifluoromethoxy, azido, —NR⁴SO₂R⁶, —SO₂NR³R⁴, —C(O)R³, —C(O)OR³,—OC(O)R³, —NR⁴C(O)OR⁶, —NR⁴C(O)R³, —C(O)NR³R⁴, —NR³R⁴, —NR⁵C(O)NR³R⁴,—NR⁵C(NCN)NR³R⁴, —OR³, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl,aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl andheterocyclylalkyl, and wherein said aryl, heteroaryl, arylalkyl,heteroarylalkyl, heterocyclyl or heterocyclylalkyl rings are optionallysubstituted independently with one or more groups selected from halogen,hydroxyl, cyano, nitro, azido, fluoromethyl, difluoromethyl,trifluoromethyl, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₃-C₆cycloalkyl, C₃-C₆ heterocycloalkyl, NR³R⁴ and OR³; R⁷ is hydrogen orC₁-C₁₀ alkyl, wherein said alkyl is optionally substituted independentlywith one or more groups independently selected from oxo (with theproviso that it is not substituted on an aryl or heteroaryl), halogen,cyano, nitro, trifluoromethyl, difluoromethyl, fluoromethyl,fluoromethoxy, difluoromethoxy, trifluoromethoxy, azido, —NR¹¹ SO₂R¹⁴,—SO₂NR¹¹R¹², —C(O)R¹¹, —C(O)OR¹¹, —OC(O)R¹¹ , —NR¹¹C(O)OR¹⁴,—NR¹¹C(O)R¹², —C(O)NR¹¹R¹², —SR¹¹, —S(O)R¹⁴, —SO₂R¹⁴, NR¹¹R¹²,—NR¹¹C(O)NR¹²R¹³, —NR¹¹C(NCN)NR¹²R¹³, —OR¹¹, C₁-C₁₀ alkyl, C₂-C₁₀alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, aryl, heteroaryl, arylalkyl,heteroarylalkyl, heterocyclyl and heterocyclylalkyl, and wherein saidaryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl orheterocyclylalkyl rings are optionally substituted independently withone or more groups selected from halogen, hydroxyl, cyano, nitro, azido,fluoromethyl, difluoromethyl, trifluoromethyl, C₁-C₄ alkyl, C₂-C₄alkenyl, C₂-C₄ alkynyl, C₃-C₆ cycloalkyl, C₃-C₆ heterocycloalkyl,NR¹¹R¹² and OR¹¹; R⁸ is Br, I or SR¹¹; R³ is hydrogen, trifluoromethyl,C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₄-C₁₀cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,heterocyclyl, heterocyclylalkyl, wherein any of said alkyl, alkenyl,alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,heterocyclyl and heterocyclylalkyl portions are optionally substitutedindependently with one or more groups independently selected from oxo(with the proviso that it is not substituted on an aryl or heteroaryl),halogen, cyano, nitro, alkyl, fluoromethyl, difluoromethyl,trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy,azido, —NR¹¹SO₂R¹⁴, —SO₂NR¹¹R¹², —C(O)R¹¹, —C(O)OR¹¹, —OC(O)R¹¹,—NR¹¹C(O)OR¹⁴, —NR¹¹C(O)R¹², —C(O)NR¹¹R¹², —SR¹¹, —S(O)R¹⁴, —SO₂R¹⁴,—NR¹¹R¹², —NR¹¹C(O)NR¹²R¹³, —NR¹¹C(NCN)NR¹²R¹³, —OR¹¹, C₁-C₁₀ alkyl,C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, aryl, heteroaryl,arylalkyl, heteroarylalkyl heterocyclyl, and heterocyclylalkyl, or R³and R⁴ together with the atom to which they are attached form a 4 to 10membered heteroaryl or heterocyclic ring, wherein said heteroaryl andheterocyclic rings are optionally substituted independently with one ormore groups independently selected from halogen, cyano, nitro,trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, —NR¹¹SO₂R¹⁴,—SO₂NR¹¹R¹², —C(O)R¹¹, —C(O)OR¹¹, —OC(O)R¹¹, —NR¹¹C(O)OR¹⁴,—NR¹¹C(O)R¹², —C(O)NR¹¹R¹², —SR¹¹, —S(O)R¹⁴, —SO₂R¹⁴, —NR¹¹R¹²,—NR¹¹C(O)NR¹²R¹³, —NR¹¹C(NCN)NR¹²R¹³, —OR¹¹, C₁-C₁₀ alkyl, C₂-C₁₀alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, aryl, heteroaryl, arylalkyl,heteroarylalkyl, heterocyclyl and heterocyclylalkyl; R⁴ and R⁵independently are hydrogen or C₁-C₆ alkyl, or R⁴ and R⁵ together withthe atom to which they are attached form a 4 to 10 membered carbocyclicring, wherein said alkyl and carbocyclic ring are optionally substitutedindependently with one or more groups independently selected fromhalogen, cyano, nitro, trifluoromethyl, difluoromethoxy,trifluoromethoxy, azido, —NR¹¹SO₂R¹⁴, —SO₂NR¹¹R¹², —C(O)R¹¹, —C(O)OR¹¹,—OC(O)R¹¹, —NR¹¹C(O)OR¹⁴, —NR¹¹C(O)R¹², —C(O)NR¹¹R¹², —SR¹¹, —S(O)R¹⁴,—SO₂R¹⁴, —NR¹¹R¹², —NR¹¹C(O)NR¹²R¹³, —NR¹¹C(NCN)NR¹²R¹³, —OR¹¹, C₁-C₁₀alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, aryl,heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl andheterocyclylalkyl; R⁶ is trifluoromethyl, C₁-C₁₀ alkyl, C₃-C₁₀cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclylor heterocyclylalkyl, wherein said alkyl, cycloalkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl portionsare optionally substituted independently with one or more groupsindependently selected from oxo (with the proviso that it is notsubstituted on an aryl or heteroaryl), halogen, cyano, nitro,trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, —NR¹¹SO₂R¹⁴,—SO₂NR¹¹R¹², —C(O)R¹¹, —C(O)OR¹¹, —OC(O)R¹¹, —NR¹¹C(O)OR¹⁴,—NR¹¹C(O)R¹², —C(O)NR¹¹R¹², —SR¹¹, —S(O)R¹⁴, —SO₂R¹⁴, —NR¹¹R¹²,—NR¹¹C(O)NR¹²R¹³, —NR¹¹C(NCN)NR¹²R¹³, —OR¹¹, C₁-C₁₀ alkyl, C₂-C₁₀alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, aryl, heteroaryl, arylalkyl,heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; R¹¹, R¹² and R¹³independently are hydrogen, lower alkyl, lower alkenyl, aryl orarylalkyl, and R¹⁴ is lower alkyl, lower alkenyl, aryl or arylalkyl, orany two of R¹¹, R¹², R¹³ and R¹⁴ together with the atom to which theyare attached form a 4 to 10 membered heteroaryl or heterocyclic ring,wherein said alkyl, alkenyl, aryl, arylalkyl, heteroaryl ring andheterocyclic ring are optionally substituted independently with one ormore groups independently selected from halogen, cyano, nitro,trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, C₁-C₁₀ alkyl,C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, aryl, heteroaryl,arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; W isheteroaryl, heterocyclyl, —C(O)OR³, —C(O)NR⁴OR³, —C(O)R⁴OR³,—C(O)NR⁴SO₂R³, —C(O)(C₃-C₁₀ cycloalkyl), —C(O)(C₁-C₁₀ alkyl),—C(O)(heterocyclyl) or CR³R⁴OR³, wherein any of said cycloalkyl, alkyl,heteroaryl and heterocyclyl portions are optionally substitutedindependently with one or more groups independently selected fromhalogen, cyano, nitro, azido, —NR³R⁴, —OR³, C₁-C₁₀ alkyl, C₂-C₁₀alkenyl, C₂-C₁₀ alkynyl, cycloalkyl and heterocycloalkyl, provided thatwhen W is C(O)OR³ and R⁹ is F, R⁷ cannot be H; m is 0, 1, 2, 3,4 or 5;and j is 0, 1 or
 2. 2. The compound of claim 1, where R⁹ is hydrogen,halogen, cyano, amino, alkyl, fluoromethyl, difluoromethyl,trifluoromethyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, oranilino.
 3. The compound of claim 2 where W is selected from heteroaryl,—C(O)OR³, —C(O)NR⁴OR³ and —C(O)NR⁴S(O)₂R³, wherein said heteroaryl isoptionally substituted independently with one or more groups selectedfrom halogen, hydroxyl, cyano, nitro, azido, fluoromethyl,difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy,difluoromethoxy, trifluoromethoxy, amino, aminomethyl, dimethylamino,aminoethyl, diethylamino, ethoxy, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄alkynyl, C₃-C₆ cycloalkyl and C₃-C₆ heterocycloalkyl.
 4. The compound ofclaim 2, where W is selected from —C(O)OR³, and —C(O)NHOR³, and R³ isselected from hydrogen, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₃-C₆cycloalkyl and C₃-C₆ heterocycloalkyl, wherein any of said C₁-C₄ alkyl,C₂-C₄ alkenyl, C₂-C₄ alkynyl, cycloalkyl or heterocycloalkyl areoptionally substituted independently with one or more groups selectedfrom —NR¹¹R¹², —OR¹¹, alkyl and cycloalkyl.
 5. The compound of claim 3,where R⁷ is C₁-C₄ alkyl, wherein said C₁-C₄ alkyl is optionallysubstituted independently with one or more groups selected from halogen,hydroxyl, cyano, nitro, azido, fluoromethyl, difluoromethyl,trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy, amino,aminomethyl, dimethylamino, aminoethyl, diethylamino, ethoxy,cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein saidcycloalkyl, heterocycloalkyl, aryl or heteroaryl rings are optionallysubstituted independently with one or more groups selected from halogen,hydroxyl, cyano, nitro, azido, fluoromethyl, difluoromethyl,trifluoromethyl, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₃-C₆cycloalkyl, C₃-C₆ heterocycloalkyl, —NR¹¹R¹², and —OR¹¹.
 6. The compoundof claim 4, where R⁷ is C₁-C₄ alkyl wherein said C₁-C₄ alkyl isoptionally substituted independently with one or more groups selectedfrom halogen, hydroxyl, cyano, nitro, azido, fluoromethyl,difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy,difluoromethoxy, amino, aminomethyl, dimethylamino, aminoethyl,diethylamino, ethoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl,wherein said cycloalkyl, heterocycloalkyl, aryl or heteroaryl rings areoptionally substituted independently with one or more groups selectedfrom halogen, hydroxyl, cyano, nitro, azido, fluoromethyl,difluoromethyl, trifluoromethyl, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄alkynyl, C₃-C₆ cycloalkyl, C₃-C₆ heterocycloalkyl, —NR¹¹R¹², and —OR¹¹.7. The compound of claim 5, where R¹ and R² are independently hydrogen,halogen, methyl, fluoromethyl, difluoromethyl, trifluoromethyl or ethyl.8. The compound of claim 5, where R¹ is halogen or methyl and R² ishydrogen.
 9. The compound of claim 8, where R¹ is halogen and R⁹ isalkyl, halogen or CN.
 10. The compound of claim 9, where R⁷ is methyl.11. The compound of claim 6, where R¹ and R² are independently hydrogen,halogen, methyl, fluoromethyl, difluoromethyl, trifluoromethyl or ethyl.12. The compound of claim 6, where R¹ is halogen or methyl and R² ishydrogen.
 13. The compound of claim 12, where R¹ is halogen and R⁹ isalkyl, halogen or CN.
 14. The compound of claim 13, wherein R⁷ ismethyl.
 15. A composition comprising a compound of claim 1 and apharmaceutically acceptable carrier.
 16. A compound selected from:2-(4-Bromo-2-fluorophenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid;5-Bromo-2-(4-bromo-2-fluorophenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid;5-Bromo-2-(4-bromo-2-fluorophenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid (2-hydroxyethoxy)-amide;2-(4-Bromo-2-fluorophenylamino)-6-oxo-1,6-dihydropyridine-3-carboxylicacid;2-(4-Bromo-2-fluorophenylamino)-6-oxo-1,6-dihydropyridine-3-carboxylicacid cyclopropylmethoxy-amide; Methyl2-(4-bromo-2-fluorophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylate;2-(4-Bromo-2-fluorophenylamino)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide;Methyl2-(2-fluoro-4-iodophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylate;(S)-2-(4-bromo-2-fluorophenylamino)-N-(2-hydroxypropoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide;and pharmaceutically acceptable salts thereof.